Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment

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For tumor antigen-specific T cells to effectively control the growth of cancer cells in vivo, they must gain access to, and function within, the tumor microenvironment. While tumor antigen-based vaccines and T cell adoptive transfer strategies can result in clinical benefit in a subset of patients, most of the patients do not respond clinically. Even for tumor-infiltrating lymphocyte (TIL)-based adoptive transfer for patients with metastatic melanoma, which can provide tumor shrinkage in around 50% of treated individuals, many patients are not eligible, in part because there are not sufficient TIL present in the resected tumor. Thus, the denominator is in fact larger, and it has been suggested that absence of TIL may be a marker for poor efficacy of immunotherapies in general. While qualitative and/or quantitative features of the T cells are important considerations for efficacy, a major component of primary resistance likely can be attributed to the tumor microenvironment. Data are accumulating suggesting that two major categories of immune resistance within the tumor microenvironment may exist: failure of T cell trafficking due to low levels of inflammation and lack of chemokines for migration, and dominant suppression through immune inhibitory mechanisms. New therapeutic interventions are being guided by these observations, and preliminary clinical success is validating this working model.

Highlights

► A T cell-inflamed tumor microenvironment may be predictive of response to immunotherapies. ► Non-inflamed tumors may require interventions directed at promoting chemokine production and T cell recruitment into tumor sites. ► T cell-infiltrated tumors appear to escape via the dominant action of immune suppressive mechanisms. ► Strategies to interfere with PD-L1/PD-1 interactions, block IDO activity, depleted Tregs, and reverse T cell anergy have been validated in animal models and are being tested clinically. ► Anti-PD-1 and anti-PD-L1 mAbs have shown impressive clinical activity in early phase clinical trials.

Section snippets

Introduction: probing the tumor microenvironment as a predictive biomarker for clinical benefit from immunotherapy

Analysis of the tumor microenvironment in a systematic fashion in patients began with the goal of identifying a predictive biomarker associated with clinical benefit to therapeutic cancer vaccines. The motivation for this pursuit was the observation that vaccine-induced immune responses as measured in the peripheral blood did not consistently correlate with anti-tumor activity. In fact, with the most potent vaccine formulations, the majority of patients indeed develop antigen-specific T cell

Tumors lacking T cell-based inflammation may require innate immune triggers to promote T cell trafficking

A working model has emerged in which one might envision the need for a distinct set of immunotherapeutic interventions dictated by the presence or absence of an immune-permissive tumor microenvironment. Developing strategies for how to manipulate non-inflamed tumors and render them permissive should benefit from a greater understanding of how a spontaneous T cell response is able to develop naturally in a subset of patients. Theoretically, in addition to the expression of (neo-)antigens that

Tumors that support T cell trafficking appear to show high expression of immune suppressive pathways that can be targeted therapeutically

If a subset of tumors does indeed support endogenous T cell priming all the way through to migration of activated CD8+ effector cells into a chemokine-rich tumor microenvironment, then it may seem paradoxical that those tumors exist at all and are not rejected spontaneously by the host. However, several small functional studies of T cells isolated from the melanoma tumor microenvironment have suggested that those specific for tumor antigens appear to be hyporesponsive [40, 41, 42].

Conclusions and future directions

Increasing our understanding of the tumor microenvironment has provided a foundation for the rational development of immunotherapeutic approaches for the treatment of cancer. As a T cell-inflamed tumor microenvironment may be a relevant predictive biomarker for clinical benefit, novel approaches to induce this phenotype as a therapeutic strategy should be pursued. Proof-of-concept approaches in preclinical models have largely been evaluated using intratumoral injection, which will not likely be

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

Data discussed in this review were supported by R01CA161005, R01CA127475, R01CA118153, P01CA97296, and the Melanoma Research Alliance. Through the course of this work, the authors have appreciated the technical support of Michael Leung, Michelle Gao, and Glee Li, as well as infrastructure support through multiple University of Chicago Comprehensive Cancer Center shared resources (Human Immunologic Monitoring and cGMP facilities, Functional Genomics Facility, Human Tissue Resource, and Flow

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