Immune–Cancer Interactions: Current Views and Clinical Applications
Today, the evidence showing that the immune system plays a central role in cancer development (either preventing or promoting cancer) is overwhelming. Many cellular and molecular immune components are involved in this process of restriction or promotion of cancer. Additionally, these interventions of the immune system can occur at different levels in or around the tumor (including genes, cells, and the tumor microenvironment) and at every step of its progression, from initiation to neoplastic progression to metastasis. For example, mouse models showed that tumor-associated macrophages promote angiogenesis and tissue remodeling, thereby favoring tumor growth. Clinical studies show that extensive tumor-associated macrophage inﬁltration positively correlates with cancer metastasis and poor clinical prognosis.
Investigations about the role of the immune system in cancer progression have led to remarkable clinical applications. For example, several groups have shown how, in a diversity of cancers, inﬁltration by certain immune components had a better prognostic value than more traditional approaches. But most crucially, since the 2010s, the knowledge accumulated over decades about immune-mediated control of cancerous tumors has turned into speciﬁc clinical applications called “cancer immunotherapies,” which many have described, rightly or wrongly, as “revolutionary”. After extremely encouraging results obtained in melanoma and a few other cancer types at the beginning of the 2010s, evidence in favor of the success of immunotherapies (increasingly, in fact, a combination of immunotherapies) in several cancers has accumulated. In a number of situations, the results have been unprecedented and sometimes even spectacular, especially in cases of previously incurable cancers, raising much enthusiasm. Immunotherapies are diverse but recently immune checkpoint inhibitors have been particularly explored.
The most signiﬁcant recognition of the work done in this area is undoubtedly the 2018 Nobel Prize in Physiology/Medicine awarded to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation,” which is centered on the blockade of immune checkpoints. This has deﬁnitely convinced researchers working in all areas of cancer investigation and the lay public that it is indispensable to pay attention to the role of the immune system in cancer. It comes as no surprise that many newspapers have discussed these medical advances, if perhaps sometimes hyperbolically.
对这一领域所做工作最重要的认可无疑是授予 James P. Allison 和 Tasuku Honjo 的 2018 年诺贝尔生理学/医学奖，“以表彰他们通过抑制负性免疫调节来治疗癌症的发现”，其重点是对于抑制性免疫检查点的阻断。这无疑使癌症科研领域和普通公众相信，关注免疫系统在癌症中的作用是必不可少的。毫不奇怪，许多媒体已经讨论了这些医学进步，即使有时可能是夸张的。
Are immunotherapies really revolutionary, and what do they tell us about immune–cancer interactions? From a strictly medical point of view, this enthusiasm is justiﬁed, although we should keep in mind that some important limits exist. The ﬁrst limit is the low percentage of responders: less than 15 percent on average, though it depends on tumor type and on the category of immunotherapy. (Future research likely will signiﬁcantly extend the proportion of responders.) A second limit is the existence of sometimes signiﬁcant adverse effects (immunotherapies, in particular, increase the level of inﬂammation and autoimmune responses, which can lead to colitis, hepatitis, etc.). A third limit is the currently exorbitant cost of some treatments.
From a conceptual viewpoint, therapies based on immune checkpoint inhibition constitute indeed a radical change in perspective. At least two important features of immune checkpoint therapies are worth emphasizing. First, the target of the treatment is the immune system, not the tumor itself (as was the intention with traditional treatments such as surgery, chemotherapy, and radiotherapy – although, in fact, some of them are now known to act at least in part via stimulation of the immune system). Second, the objective is to break the state of immune tolerance that has been established between the tumor and the immune system in the local tissue – partly as a consequence of the chronic expression of cancer antigens. More precisely, the aim with immune checkpoint blockers is to downregulate inhibitory signals in tumor–immune interactions. This constitutes a move from enhancement of the immune system to “normalization” of the immune system: in immune checkpoint inhibitor-based immunotherapies, especially with anti-PD-L1, the aim is not, strictly speaking, to boost the immune system beyond its normal rate of activation but to restore a local context in which the immune system will be able to act as it normally does.
Together, basic studies about the role of the immune system in cancer and clinical studies in the domain of immunotherapies also have contributed to an important change in perspective about what cancer is and how it develops. It is increasingly recognized that tumor-centric views of cancer (with genetic mutations seen as the main cause of cancer) are insufﬁcient: to understand (and cure) cancer, it is essential to consider not only the tumor itself but also the tumor environment. The tumor environment includes the tissue context located at the vicinity of the tumor (sometimes called the tumor microenvironment), but also elements located quite remotely from the tumor in the organism (such as some immune-associated organs and the microbiota, which recently has been proven to inﬂuence cancer progression and therapies). Even authors who initially focused on intrinsic molecular aspects of cancer development have later emphasized the importance of the tumor microenvironment. Targeting the tumor microenvironment also offers enriched therapeutic strategies. There is a growing consensus that the immune system plays a crucial role in the tumor microenvironment. In fact, given the centrality of immune components in the organization of, and control over, the local tissue, it seems reasonable to say that every cancer involves the immune system, which necessarily intervenes, at one point or another, in the shaping of the local context that enables the tumor to emerge, grow, and perhaps spread.
The idea that cancer constitutes a breakdown of biological individuality is widespread in the scientiﬁc and philosophical literature. Biologist Leo Buss was instrumental in showing that biological individuality in multicellular organisms must be understood as an outcome of evolution, by which, on several occasions in life’s history, some cells aggregated and cooperated, and in which emerged some control mechanisms over cells that would proliferate at the expense of the whole organism. Buss takes cancer as an example of a decohesion of the biological individual, in which cancer cells are “re-individualized” in a way that becomes harmful to the multicellular organism. This idea has subsequently been explored by several biologists and philosophers of biology, often inspired by the study of clonal evolution at the cell level in cancer. For example, Godfrey-Smith labels as “de-darwinization” the process by which a higher-level individual prevents proliferation of lower-level individuals. From that point of view, cancer cells appear as a result of a “re-darwinization” at the cell level.
癌症使生物个体崩溃的观点在科学和哲学文献中广为流传。生物学家 Leo Buss 在证明多细胞生物体的生物个体性必须被理解为进化的结果方面发挥了重要作用，在生命的历史中，多个细胞聚集和相互作用，形成多细胞生物个体，并在个体中出现了一些控制细胞增殖的机制 ，以避免细胞“外溢”，而“侵害”整个生物体。Buss 将癌症作为生物个体退化的一个例子，其中癌细胞以对多细胞生物个体有害的方式“重新个体化”。这个想法随后被几位生物学家和生物学哲学家探索，通常受到癌症细胞水平克隆进化研究的启发。例如，戈弗雷-史密斯将高级个体阻止低级个体增殖的过程称为“去达尔文化”。从这个角度来看，癌细胞的出现是细胞水平“达尔文进化论”的结果。
However, the mechanistic details by which the multicellular organism exerts control over cancer cells have remained vague. Michod cites programmed cell death and the immune system as the two main “policing mechanisms” in the multicellular organism, but he does not give any detailed explanation about how they work. An important lesson of what has been said in this section is that immunological surveillance constitutes a convincing example of a mechanistically precise process of maintenance of cohesiveness in the organism. Thus, it offers an important contribution to this long-standing debate concerning de-darwinization in cancer. The details of how immune-mediated control works are well documented: in the elimination phase of immunoediting, myriad immune cells and molecules (macrophages, dendritic cells, NK cells, γδ T cells, CD4 and CD8 T cells, IFN-γ, among many others) contribute to the destruction of the tumor. In addition, immune-mediated control contributes to coordinate other control instruments, such as apoptosis and angiogenesis.
然而，多细胞生物个体对癌细胞施加控制的机制细节仍然模糊。 Michod 将程序性细胞死亡和免疫系统列为多细胞生物个体中的两个主要“监管机制”，但他没有对它们的工作原理给出任何详细解释。本节中所说的一个重要教训是，免疫监视构成了一个令人信服的例子，说明了机体内聚性维持的机械精确过程。因此，它为这场关于癌症去达尔文化的长期争论做出了重要贡献。免疫介导控制如何工作的细节有据可查：在免疫编辑的消除阶段，无数免疫细胞和分子（巨噬细胞、树突状细胞、NK 细胞、γδ T 细胞、CD4 和 CD8 T 细胞、IFN-γ 及其他）有助于破坏肿瘤。此外，免疫介导的控制有助于协调其他控制工具，例如细胞凋亡和血管生成。
This, however, strengthens rather than solves the paradox: if immune-mediated restriction is one of the main mechanisms ensuring the cohesion of the organism, we need an explanation for why in some circumstances the immune system favors tumor development (through the escape phase of immunoediting and/or through repair mechanisms that contribute to creating a favorable tissue environment for the tumor). To better understand this phenomenon, I propose here an extended view of immune-mediated cohesion and decohesion.
The traditional view about immune-mediated cohesion, as represented in classically deﬁned immunological surveillance, is that the immune system can eliminate abnormal cells such as cancer cells (Figure 4.2).
Figure 4.2 The traditional view of immune-mediated cohesion, as proposed by the immunological surveillance hypothesis. According to this view, the immune system directly eliminates abnormal cells, such as cancer cells (in red) in the tumor.
This view, however, is too narrow, because it neglects the diversity of activities in which the immune system is involved, which include not only defense but also development, tissue repair, clearance of debris, and maintenance of tissue homeostasis, among others. In cancer, many of these immunological activities are found. This leads to a much richer view of immune-mediated cohesion and decohesion in cancer (Figure 4.3). In this view, the immune system plays a major role in regulation of the organization of the local tissue, and, together, the immune system and the tissue realize different activities, including the elimination of abnormal cells, but also the containment of abnormal cells (in that case, cells are not destroyed, they are simply kept under control, which limits the damage they can do and/or their capacity to spread), the maintenance of chronic elements present in the local environment (most of the time, these chronic elements are normal self components of the organism, but chronically present tumor constituents can also lead to active maintenance of the tumor by the immune system, which progressively sees these elements as normal) (Pradeu et al. 2013; Pauken and Wherry 2015), and the repair of the local tissue (in physiological conditions, this repair is a necessary process insuring the integrity of the tissue, but in the context of cancer repair mechanisms can favor cancer progression).
Figure 4.3 A richer view of immune-mediated cohesion and immune-mediated decohesion in cancer. In this view, the immune system controls tissue organization and, together, the immune system and the local tissue can exert a variety of cohesion-promoting activities, including the elimination of abnormal cells, but also the containment of abnormal cells, the maintenance of chronic elements, and tissue repair. All these activities (not just elimination), in pathological conditions, can promote decohesion of the organism.
The crucial point here is that decohesion as seen in cancer can concern all these different activities, not just elimination: the immune system, which in most cases prevents cancer progression by elimination, containment, maintenance, and repair, can in some circumstances promote cancer progression because of deregulated elimination, containment, maintenance, and/or repair. Moreover, all these activities must be understood diachronically: they do not all intervene at the same time, and the immune system can switch from one effect to the other (for example, it can initiate the destruction of abnormal components and later contribute to their maintenance because they have become chronically expressed in the tissue).
Does the immune system dysfunction when it promotes cancer progression via a deﬁcit in elimination or containment and/or via maintenance processes and/or via repair processes? I suggest distinguishing two situations here. The ﬁrst situation corresponds to a dysfunctional immune system. An organism, either structurally or provisionally (e.g., after a treatment with immunosuppressive drugs), can have a defective immune system (e.g., a deﬁcit in effector T cells, or a disequilibrium in the respective numbers of its inﬂammatory and regulatory macrophages – or, more speciﬁcally, of its macrophages distributed along the inﬂammatory to “alternatively activated” spectrum). Such abnormalities can contribute to explain the triggering of cancer, and they could be targeted by a number of therapies, which precisely aim at correcting these immune defects.
当免疫系统促进癌症进展时，无论是因为消除或遏制癌症的缺陷，还是通过免疫耐受的维护和/或机体修复机制，此时的免疫系统是否存在功能障碍？我建议在这里区分两种情况。第一种情况免疫系统的功能失调。一个生物体，无论是结构上的还是暂时的（例如，在用免疫抑制药物治疗后），都可能有一个有缺陷的免疫系统（例如，效应 T 细胞的缺陷，或其炎症性和调节性巨噬细胞的比例失衡——或者， 更具体地说，它的巨噬细胞处于炎症和“不稳定活跃”的状态）。这种异常有助于解释癌症的触发，并且很多免疫疗法都旨在纠正这些免疫缺陷。
In the second situation, however, the immune system acts normally and immune-mediated decohesion is due to an abnormal context. Pathogens, wounds, mechanical pressure, and local modiﬁcations due to carcinogenic environmental factors, among several other causes, can create an abnormal local context (characterized by inﬂammation, perturbation of the extracellular matrix, and so on). This local context inﬂuences the immune system, which in turn responds as it usually does, that is, by maintaining or repairing the tissue – even if the ﬁnal, pathological, outcome is cancer promotion (Figure 4.4). It has long been known, for instance, that tumors resemble “wounds that do not heal”, which means that, in cancer, normal repair mechanisms are triggered but generally without reaching the “resolution phase” (which, in the physiological context, is indispensable to terminate the reparative process). Furthermore, the tumor itself can be a major source of perturbation of the local context: it can inﬂuence the immune system through a variety of cytokines and can also increase inﬂammation and wounding, modify blood vessels, reshape the extracellular matrix, or exert a mechanical pressure, among many other possibilities. This is often described as the “hijacking” or “co-option” by the tumor of physiological pathways and of the tissue microenvironment. Despite its importance, one must keep in mind that such co-option is only one of the many ways in which the local context can become abnormal and favor the contribution of immune processes to cancer progression.
Figure 4.4 Decohesion in cancer induced by an abnormal context. Immune-mediated decohesion may be due to an abnormal context rather than an abnormal immune system. This abnormal context can be due to the presence of pathogens, wounds, mechanical pressures, and carcinogens of environmental origins, among many other resources; it can also be triggered by the tumor itself. In many situations, the decohesion mediated by the immune system results from abnormal realization of normal processes (such as maintenance and repair).
In all these contexts, immune-mediated decohesion results from the abnormal realization of normal processes, and this can help explain why tumors largely resemble organs and are the products of classic developmental and reparative pathways realized in an abnormal context. There is no doubt that the outcome is pathological (the promotion of a cancerous tumor, including in some cases metastatic spread), but the immune system, in many of these circumstances, does not strictly speaking “dysfunction”; it just does what it always does (maintaining the local environment, repairing in case of wound, etc.).
If the view presented here is correct, then a much richer picture emerges about how the immune system inﬂuences cancer and, ultimately, of potential therapeutic opportunities as well. Indeed, the immune system inﬂuences cancer through different processes (elimination, containment, maintenance, repair, and so on), via many actors (not only lymphocytes, but also macrophages, neutrophils, and various cytokines), at several different levels (within the tumor, but also around the tumor, in the whole tissue, and at a systemic level in the organism), and at all temporal stages of cancer progression (initiation, neoplastic progression, and metastasis). Additionally, the inﬂuence of the immune system on the cancerous tumor can be negative (the immune system prevents cancer progression) or positive (the immune system promotes cancer progression).
All this suggests a whole series of new opportunities for investigating immunotherapies, which could, at least in principle, target these different processes, actors, levels, and temporal stages. Current immunotherapies (particularly immune checkpoint inhibitors and CAR-T cells) focus on lymphocytes in terms of actors and on elimination and maintenance and rupture of chronicity in terms of processes, but many other possibilities exist. Depending on where we are in the cycle of cancer–immune system interactions and on the actors of the tumor microenvironment involved, some therapeutic strategies will aim at normalization while others will aim at denormalization. Examples of normalization include the reduction of the level of inﬂammation in the tissue, the elimination of pathogens and/or chronic wounds, the restoration of immune accessibility to the tumor, and the facilitation of the resolving phase of tissue repair. In contrast, denormalization would be a major aim when the immune system interacts with tumor components as if they were normal constituents of the body, as, for example, when the immune system is tolerogenic in the context of chronically present tumor antigens or when the immune system continuously triggers repair pathways to respond to a local cancerous context that displays many features usually associated with a wound.
In summary, this section has shown that focusing on the immune system is essential for anyone studying cancer. Cancer is a disease of multicellularity and, more speciﬁcally, of the cohesion of the multicellular organism. Immunological surveillance constitutes one of the main and best described mechanisms by which the multicellular organism exerts control over lower-level entities. A major result of recent research is that the immune system can both restrain and promote cancerous tumors, which may seem, at ﬁrst sight, paradoxical. Yet the situation becomes less paradoxical when one realizes that immune-mediated decohesion is often due to an abnormal context rather than a dysfunctional immune system. We have suggested here an extended view of cancer–immune interactions, which opens up many opportunities for investigating new mechanisms of tumor control and tumor promotion and, ultimately, for developing novel therapeutic opportunities based on the action of the immune system.
总而言之，本节表明，关注免疫系统对于任何研究癌症的人来说都是必不可少的。癌症是一种多细胞疾病，更具体地说，是多细胞生物体凝聚（cohesion of the multicellular organism）的疾病。免疫监视（immunological surveillance）构成了多细胞生物对低级实体施加控制的主要机制之一，也是描述得最好的机制。最近研究的一个主要结果是免疫系统可以抑制和促进癌性肿瘤，乍一看，这似乎是自相矛盾的。然而，当人们意识到免疫介导的脱散（decohesion）通常是由于异常环境而不是免疫系统的功能失调引起时，情况就变得不那么矛盾了。我们在这里提出了癌症-免疫相互作用的扩展观点，这为研究抑瘤和促瘤的新机制以及开发新的免疫疗法提供了思路。