Genomic Approaches to Understanding Response and Resistance to Immunotherapy

Abstract

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly. Genomics-based approaches have significantly advanced the study of response and resistance to immunotherapy in general, and to immune checkpoint blockade more specifically. Here, we review how genomic and transcriptomic approaches have identified both somatic and germline positive correlates of response, including high mutational/neoantigen load and low intratumoral heterogeneity, among others. The genomic analysis of resistant tumors has additionally identified crucial factors involved in resistance to immune checkpoint blockade, including loss of PTEN and upregulation of other immune checkpoints. Overall, the continued use of genomic techniques at the point of care, combined with appropriate functional studies, would ideally lead to a better understanding of why certain patients respond to immune-based therapies, allowing clinicians to identify the subset of patients likely to benefit from such therapy, and potentially providing insight into how other therapies may be added in combination to increase the number of patients who may benefit from immunotherapy. Clin Cancer Res; 22(23); 5642-50. ©2016 AACR.

Figure 1. Genomic Correlates of Response

Genomics-based approaches and other investigations have led to the identification of multiple mechanisms of response to immune checkpoint blockade, including high mutation and neoantigen load, low intratumoral heterogeneity, infiltration with a clonal T cell popular, and deficiencies in DNA repair machinery.

Figure 2. Generation of Neoantigens

Wild-type antigens are recognized as “self”, and do not generate an immune response. Nonsynonymous mutations may lead to an altered peptide sequence that is ultimately presented on MHC molecules. This altered peptide sequence therefore produces a new or “neoantigen”, which may then be recognized by the host immune system, leading to an anti-tumor immune response.

Figure 3. Mechanisms of Resistance

Genomic techniques have contributed to the identification of multiple mechanisms of resistance to immune checkpoint blockade, including alterations in signaling pathways involved in cell proliferation of and apoptosis, stabilization of immune checkpoints, and alterations in MHC-peptide presentation.