Understanding the tumor immune microenvironment (TIME) for effective therapy

Abstract

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Fig. 1. General classes of TIME

Three classes of TIME are displayed. a, I-E TIMEs are characterized by the exclusion of CTLs from the tumor core. CTLs in I-E TIMEs are instead present along the tumor periphery, where they can be found in contact with Ly6C^lo F4/80⁺ tumor-associated macrophages or ‘stuck’ in fibrotic nests. b, In comparison, I-I TIMEs are defined by an abundance of PD-L1 expression on tumor and myeloid cells and highly activated CTLs characterized by expression of Grzb, IFNγ and PD-1. In some subsets of I-I TIME, tumor cells will have defects in DNA mismatch repair (MSI-H), thus resulting in an increased number of neoepitopes. c, TLS-TIMEs have histological evidence of containing TLSs, aggregates of immune cells with a composition similar to that in lymph nodes, including B cells, dendritic cells and T_reg cells.

Fig. 2. How tumor genotypes and phenotypes shape the TIME

a, Tumors are known to establish protumoral and immunosuppressive environments to support their growth and promote immune evasion. Central to building an immunosuppressive TIME are oncogenes and aberrant signaling pathways that lead to the production of cytokines and chemokines with potent effects. The tumor shown is representative of a spectrum of cancer types. In melanoma, BRAF^V600E (green triangle) has been shown to induce constitutive WNT/β-catenin signaling, which in turn decreases production of CCL4, a chemokine important for the recruitment of CD103⁺ DCs. Additionally, BRAF^V600E has been shown to induce expression of factors such as IL-10 and IL-1α, which can induce tolerogenic forms of DC and cancer-associated fibroblasts (CAFs), respectively. Oncogenic KRAS^G12D in PDAC leads to the secretion of GM-CSF, corresponding to increased development of CD11b⁺ myeloid cells with reported immunosuppressive function. Deficiency in p53 in hepatic stellate cells, a stromal population, leads to production of factors that polarize TAMs from the immunoactivating M1 phenotype to the immunosuppressive M2 phenotype. Interestingly, many tumors have been shown to secrete high levels of the monocyte/macrophage-promoting cytokine CSF-1. b, The mutational landscape of tumors can profoundly affect the quality and character of the TIME. In CRC, there are four consensus molecular subtypes (CMS1-4). CMS1 is defined by defects in DNA mismatch repair leading to microsatellite instability or hypermutation rates. Because of the abundance of possible neoepitopes, CTL infiltration is generally high, and CTLs display gene expression patterns indicative of an ongoing immune response. Patients with CMS1 tumors have generally more favorable outcomes with checkpoint-blockade treatment than do patients with CMS2-4. Although there are differences in the histological and immunological character of CMS2, 3 and 4 CRC subtypes, they are generally less immune infiltrated, as is suggestive of antigenically cold tumors.

Fig. 3. Character of the TIME during progressive tumor development

a, A major contributing factor in the failure to immunologically reject tumors stems from induction of T cell exhaustion, a state in which T cells become less responsive to antigens and are ineffective at providing T cell help or eliminating appropriate targets. Recent evidence suggests that T cell exhaustion occurs rapidly after oncogenic initiation, possibly because of chronic antigen exposure on tumor cells. As a T cell transitions from effector (T_eff) to exhausted (T_ex), there is increased expression of exhaustion-associated molecules such as LAG3, 2B4 and TIM3, and downregulation of effector cytokines such as IFNγ. From a therapeutic standpoint, epigenetic evidence suggests that there are types of T cell exhaustion that are irreversible, thus potentially explaining why some patients are completely unresponsive to some forms of ICB. APC, antigen-presenting cell; pMHC, peptide-bound major histocompatibility complex; TCR, T cell receptor. b, During tumor development, progressive changes in the character and quality of the TIME occur that coincide with disease severity and influence responsiveness to therapeutics. Recent evidence in mice suggests that YS-TAMs are more potently immunosuppressive than their monocyte-derived counterparts (TAMs). Whereas TAMs have been shown to suppress CD103⁺ DCs through secretion of IL-10, only depletion of YS-TAMs in a model of PDAC has been found to lessen tumor burden. Because YS-TAMs are theoretically present in the tumor site during oncogenic initiation, they may make the first contact with antitumor T cells and may be responsible for early T cell exhaustion. As tumors progress, TAMs of both types expand, whereas T_eff cells slowly become T_ex cells, and stimulatory CD103+ DCs become a more marginal and rare population. During metastatic seeding, pioneering metastatic tumor cells arrive and die. Their debris is taken up by distinct waves of myeloid cells, with monocytes and macrophages being the dominant phagocytes in the premetastatic site. CD103⁺ DCs have been shown to uptake minimal tumor debris/antigen, and this process is thought to partially contribute to reduced antitumor T cell priming. Whereas populations such as neutrophils have been associated with both metastatic success and failure, macrophages are often ascribed a prometastatic function, because their absence leads to pronounced metastatic failure. Mac, macrophage; mono, monocyte; nc mono, nonclassical monocyte.