ReviewCancer

The hallmarks of successful anticancer immunotherapy

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Science Translational Medicine  19 Sep 2018:
Vol. 10, Issue 459, eaat7807
DOI: 10.1126/scitranslmed.aat7807

Abstract

Immunotherapy is revolutionizing the clinical management of multiple tumors. However, only a fraction of patients with cancer responds to immunotherapy, and currently available immunotherapeutic agents are expensive and generally associated with considerable toxicity, calling for the identification of robust predictive biomarkers. The overall genomic configuration of malignant cells, potentially favoring the emergence of immunogenic tumor neoantigens, as well as specific mutations that compromise the ability of the immune system to recognize or eradicate the disease have been associated with differential sensitivity to immunotherapy in preclinical and clinical settings. Along similar lines, the type, density, localization, and functional orientation of the immune infiltrate have a prominent impact on anticancer immunity, as do features of the tumor microenvironment linked to the vasculature and stroma, and systemic factors including the composition of the gut microbiota. On the basis of these considerations, we outline the hallmarks of successful anticancer immunotherapy.

INTRODUCTION

Over the past decade, several immunotherapeutic agents have become available for the routine clinical management of cancer (1). These include (but are not limited to) various immune checkpoint blockers (ICBs) targeting cytotoxic T lymphocyte–associated protein 4 (CTLA4), programmed cell death 1 (PDCD1; best known as PD-1) or its main ligand (CD274; best known as PD-L1) (2), as well as autologous T cells engineered to express a CD19-targeting chimeric antigen receptor (CAR) (3). ICBs used as stand-alone therapeutic interventions elicit durable objective responses in patients affected by a variety of cancers, including melanoma, non–small cell lung carcinoma (NSCLC), urothelial carcinoma, and Hodgkin’s lymphoma (47). Along similar lines, CD19-specific CAR T cells have pronounced clinical activity in patients with B cell acute lymphoblastic leukemia (ALL) exhibiting innate or acquired resistance to standard treatment, as well as in adult patients with relapsed or refractory large B cell lymphoma (8). Other anticancer immunotherapies are currently being investigated in clinical trials, encompassing a multitude of immunostimulatory monoclonal antibodies (mAbs), small molecules that reverse cancer-associated immunosuppression, as well as multiple tumor-targeting therapeutic vaccines (9). Many of these agents are in relatively advanced phases of clinical development, suggesting that the number of immunotherapeutic strategies licensed for the clinical management of cancer will increase in the near future.

The fraction of patients who respond to ICBs used as stand-alone therapeutic interventions is generally around 20% for the most common solid tumors, although it varies greatly in different oncologic indications (46). Moreover, ICBs are associated with moderate-to-severe immunological toxicities that—at least in some cases—require treatment discontinuation and/or active management, generally with glucocorticoids (10). Finally, the cost of ICB-based immunotherapy has been estimated at 100,000 to 250,000 USD per patient (depending on the specific ICB, administration protocol, and treatment duration) (11). The fraction of patients responding to CD19 CAR T cells used as an on-label intervention is remarkably high (around 80%) (12). However, these patients may experience relatively severe neurological events or cytokine release syndromes that need to be managed with the interleukin 6 receptor (IL-6R) blocker tocilizumab (8). Moreover, CD19 CAR T cells are currently provided at more than 350,000 USD per full treatment (although some companies charge responders only) (8). Similar considerations of toxicity and cost apply to many (if not all) anticancer immunotherapies in clinical development. A variety of combinatorial approaches is being investigated to increase the fraction of cancer patients responding to immunotherapy and/or to limit side effects (13). In addition, considerable efforts are being devoted to the identification of biomarkers with robust predictive value (14). Here, we attempt to define the hallmarks of successful anticancer immunotherapy as we analyze the promise and obstacles for these features to become part of clinical decision-making in the near future.

HALLMARKS OF MALIGNANT CELLS

The success of anticancer immunotherapy depends to a large degree on the features of cancer cells that determine (i) their intrinsic potential to initiate a tumor-targeting immune response, (ii) their ability to establish an immunosuppressive tumor microenvironment (TME), and (iii) their sensitivity to immune effector mechanisms (Fig. 1).

Fig. 1 Malignant cells in the regulation of tumor-targeting immune responses driven by immunotherapy.

Several aspects of the biology of malignant cells affect the likelihood of anticancer immunotherapy to elicit robust clinical responses. During initiation (left), the abundance of tumor neoantigens (TNAs), which to some extent depends on mutational load, their quality (notably their resemblance to viral antigens), and the ability of malignant cells to emit danger signals as they die have a major influence on the elicitation of anticancer immunity by dendritic cells (DCs) and other antigen-presenting cells. Moreover, cancer cells compete for nutrients with immune effector cells and express co-inhibitory ligands and other factors including CD73 and lactate that mediate local immunosuppression (regulation; middle). Finally, during execution (right), the ability of cancer cells to properly present tumor neoantigens, respond to interferon gamma (IFN-γ) and granzyme B (GZMB), undergo regulated cell death (RCD), or mount cytoprotective autophagic responses determines their sensitivity to immune effectors. IFNGR, interferon gamma receptor; TME, tumor microenvironment.

CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

Immunogenicity

Successful adaptive immune responses against cancer cells often target tumor neoantigens, which can arise as a consequence of somatic, tumor-specific nonsynonymous DNA mutations (15). In line with this notion, a high mutational load (which increases the likelihood for the emergence of neoantigens) as well as an increased abundance of predicted tumor neoantigens have been associated with improved sensitivity to ICB-based immunotherapy in a variety of clinical settings (1618). In addition, high mutational burden has recently been attributed robust predictive value for clinical responses to ICB-based immunotherapy in patients with lung cancer (19, 20). Along similar lines, elevated degrees of genomic instability, such as those displayed by tumors with high microsatellite instability (MSI-H) or defects in mismatch repair (MMR-D), have been linked to improved disease outcome in cancer patients treated with ICBs (21), presumably reflecting the increased propensity of these neoplasms to accumulate nonsynonymous mutations. Notably, this latter discovery led to the first-in-history U.S. Food and Drug Administration (FDA) approval of pembrolizumab (a PD-1–targeting ICB) for the treatment of MSI-H or MMR-D tumors irrespective of anatomical site (21).

That being said, the quality of tumor neoantigens—a parameter linked to their dissimilarity from “self” (often along with some degree of homology to microbial antigens), and hence to their likelihood to be recognized by the mature T cell receptor (TCR) repertoire—appears to be more important than their abundance in determining the success of anticancer immunotherapy, at least in some settings (22, 23). Indeed, T cell clones potentially recognizing tumor neoantigens that are highly homologous to self-antigens are likely to undergo negative selection within the thymus (and therefore be missing from the peripheral TCR repertoire) (24). Adaptive immune responses driven by immunogenic chemotherapy and radiation therapy also appear to rely on (at least some degree of) pathogen mimicry. In this setting, cancer cells succumbing to treatment in the context of stress responses release a panel of endogenous molecules that operate as adjuvants, including (but not limited to) adenosine 5′-triphosphate (ATP) downstream of autophagy activation, calreticulin (CALR) downstream of endoplasmic reticulum stress, and type I interferon (IFN) downstream of Toll-like receptor 3 (TLR3) or cyclic GMP-AMP synthase (CGAS) signaling (25). Preclinical and clinical data suggest that the acute and robust activation of these pathways, which are intimately involved in the control of viral replication (26), plays a major role in the establishment of anticancer immunity (27, 28). Accordingly, autophagy inhibition downstream of cancer-germline antigen expression has recently been associated with clinical resistance to CTLA4 blockade in melanoma patients (29). However, biomarkers of chronic type I (and type II, see below) IFN signaling have also been linked with limited tumor sensitivity to ICBs in the clinic (30). Moreover, reflecting the robust antiviral effects of this pathway, accumulating evidence suggests that the success of oncolytic virotherapy could be compromised by proficient type I IFN responses (31). These considerations demonstrate two points that must be taken into careful consideration as predictive biomarkers for cancer immunotherapy are developed and interpreted: (i) The acute versus chronic activation of some signaling pathways may have opposite effects on anticancer immune responses, and (ii) the influence of a specific process on distinct forms of immunotherapy may exhibit a large degree of heterogeneity.

Immunosuppression

Cancer cells establish local and systemic immunosuppression via a variety of mechanisms, all of which can affect the clinical success of immunotherapy. Perhaps the most studied of these mechanisms is the expression of surface molecules that drive tumor-infiltrating CD8+ T cells and natural killer (NK) cells into exhaustion, such as PD-L1 (13). In some indications including NSCLC patients treated with ICBs, PD-L1 expression on malignant cells bears robust predictive information (5, 32). Accordingly, the immunohistochemical assessment of membranous PD-L1 levels on cancer cells is approved by the FDA as a companion diagnostic for PD-1–targeting ICBs (33). However, the actual predictive value of PD-L1 expression by neoplastic cells in other clinical settings remains to be elucidated. Similarly, whether PD-L1 expression should be harnessed as a direct mechanistic target for treatment versus a surrogate biomarker of ongoing anticancer immunity has not been conclusively demonstrated yet. PD-L1 expression by cancer cells is particularly sensitive to interferon gamma (IFNG), which is one of the major effectors of tumor-targeting immune responses (34). This suggests that PD-L1 expression (by cancer cells or immune cells) may have predictive value (at least in patients affected by some tumors) only when measured before treatment.

Another example of the mechanisms whereby malignant cells establish local immunosuppression involves 5′-nucleotidase ecto (NT5E; best known as CD73), a plasma membrane protein that participates in the conversion of extracellular ATP, which has robust chemotactic effects and potently activates DCs, into adenosine, which inhibits immune responses by a variety of mechanisms, hence controlling the balance between immunostimulatory adrenergic signaling and its immunosuppressive adenosinergic counterpart (35). In line with this notion, high expression of CD73 has been associated with poor disease outcome in triple-negative breast cancer patients receiving adjuvant immunogenic chemotherapy (36). Preclinical data supporting the importance of proficient adrenergic signaling in the TME and pointing to CD73 as a potential target for novel anticancer immunotherapies are accumulating (37, 38). In this context, it will be important to determine the relative contribution of CD73 to immunosuppression in settings in which malignant cells express high levels of PD-L1 and other ligands for co-inhibitory receptors on T cells.

Activated lymphocytes resemble cancer cells in their high metabolic demands to support intensive proliferation (39). Accordingly, cancer cells and lymphocytes engage in a metabolic competition that influences the overall immunological status of the TME (and hence the likelihood for efficient anticancer immune responses) (40). Such a competition not only is centered around glucose, whose availability in the TME is critical for cytotoxic T lymphocyte (CTL) expansion and antitumor efficacy (40, 41), but also involves multiple amino acids including glutamine and arginine (42). Several other factors that influence the competition for nutrients in the TME have just begun to emerge (42). Malignant cells also secrete a variety of metabolites and cytokines that support local and systemic immunosuppression, including (but not limited to) lactate, IL-10, and transforming growth factor beta 1 (TGFB1; best known as TGF-β1) (4345). However, the most prominent source of immunosuppressive cytokines is often tumor-infiltrating immune cells and/or stromal cells (see below).

Susceptibility

The susceptibility of cancer cells to immune effector mechanisms is essential for the success of anticancer immunotherapy. Accordingly, inactivating mutations of beta 2 microglobulin (B2M), encoding a core component of the major histocompatibility complex (MHC) class I antigen presentation machinery that is required for CD8+ T cells to recognize and kill cancer cells, as well as specific MHC class I genotypes have been linked with reduced susceptibility to ICB-based immunotherapy in cohorts of melanoma and NSCLC patients (4650). Along similar lines, genetic and epigenetic alterations affecting the interferon gamma receptor (IFNGR) signaling pathway in malignant cells, including (but not limited to) JAK1, JAK2, and APLNR mutations, have been associated with resistance to ICB in a variety of preclinical and clinical settings (48, 5154). Finally, proficient autophagic responses appear to limit the sensitivity of malignant cells to NK cell–dependent cytotoxicity, at least in part owing to the ability of autophagy to degrade the cytolytic molecule GZMB (55, 56). Although no immunotherapy specifically targeting NK cells is currently approved for clinical use, this latter observation may be of significance for agents that were conceived as targeted therapies but eventually turned out to engage innate immune effectors, such as the FDA-approved agents rituximab and trastuzumab (57). Allele-specific MHC loss as well as genetic defects in B2M and caspase 8 (CASP8), which encodes one of the mediators of apoptotic cancer cell death induced by CD8+ T cells, are common driver events in NSCLC (49, 58). This suggests that developing tumors are advantaged by mutations that render them less susceptible to CTL-mediated killing also in the absence of treatment. However, genetic alterations in MHC class I–coding loci as well as B2M and CASP8 mutations have been linked with increased mutational load and an immunological score that predicted clinical responses to ipilimumab among melanoma patients (59, 60). Moreover, CASP8 mutations have recently been associated with high amounts of intratumoral leukocytes across all cancers (61). Thus, it is tempting to speculate, but remains to be formally elucidated, that tumors evading cell-intrinsic oncosuppression and the effector arm of immunosurveillance may accumulate mutations at an increased pace. That said, how CD8+ T cells reactivated by ipilimumab would recognize and kill malignant cells bearing B2M or CASP8 mutations is an open conundrum. As a possibility, the inhibition of CTLA4 in the context of robust infiltration by CD8+ T cells (such as in tumors with CASP8 mutations) (61) may enable some degree of nonspecific activation, reminiscent of the mechanism of action of bispecific T cell engagers, (62), perhaps linked to indirect, IFNG-driven cytotoxicity via myeloid cells. This hypothesis has not been addressed experimentally yet.

As part of the identification of predictive biomarkers for anticancer immunotherapy, great