The Cancer Immunotherapy Revolution: Mechanistic Insights

Abstract

W ith this editorial, I am pleased to introduce " The Cancer Immunotherapy Revolution: Mechanistic Insights, " the second topical issue of reviews published in The Journal of Immunology. In acknowledgment of the growing interest in immuno-oncology and building on the success of our first topical issue of Brief Reviews, " The Macro Influence of the Microbiome, " we now publish a series of 10 Brief Reviews and 1 Translating Immunology article highlighting the principles, applications, and challenges im-munologists and cancer specialists face in this new era of tumor immunology and its clinical partner, cancer immu-notherapy. Finn sets the stage for this topical issue by tracing the evolution of the concept of immunosurveillance through its " in-and out-of-favor " phases and discussing how the modern techniques of immunotherapy seek to stimulate the process through which the immune system scans for damage inflicted by nascent tumors (1). Authors Zamora, Crawford, and Thomas focus on the antigenic targets of tumor-specific T cell activity and the ways by which antigenic cross-reactivity and immunodominance may modulate tumor immunity medi-ated by endogenous T cells (2). T cell repertoire and tumor mutation profiles aside, Sugiura and Rathmell discuss the metabolic barriers to efficacious T cell function erected by the acidic and hypoxic tumor microenvironment (TME) that is stingy on nutrients and awash with metabolic waste products (3). It is clear that promoting the elimination of solid tumors will require tools to relieve the defective metabolic re-programming of intratumoral T cells imposed by the im-munosuppressive TME. Nixon and Li emphasize that T cells are not the only tumor-infiltrating cytolytic cells. Tumor-resident innate lymphoid cells of ill-defined lineage receive signals derived from IL-15 and stress-associated ligands that promote their proliferation and cytolytic capacity (4). Har-nessing the antitumor activity of these still mysterious but likely critical first responders will require continued research to better understand how their responses can be modulated. Tumors are populated not only by lymphocytes bent on tu-mor elimination, but also by cells with recognized immuno-suppressive activity. Chao and Savage review our current understanding of tumor-associated regulatory T (Treg) cell control and function, including their conserved tumor-specific transcriptional signature and associated molecular programs, knowledge that may pave the way for specifically targeting the activity of intratumoral Treg cells (5). These authors emphasize that assessing the risks inherent in modu-lating tumor-infiltrating Treg cell function requires further investigation into the little-studied activities of intratumoral Treg cells that extend beyond dampening antitumor re-sponses. Myeloid-derived suppressor cells (MDSCs) also contribute to the suppressive intratumoral environment, and are the subject of a review by Ostrand-Rosenberg and Fen-selau (6). These heterogeneous and developmentally imma-ture myeloid cells are responsive to tumor-derived growth factors, chronic inflammation, and proinflammatory media-tors such as PGE 2 , calcium-binding proteins, and cytokines such as IL-6 and IL-1b that promote their intratumoral ac-cumulation and suppressive function. MDSCs mediate sup-pression in part by enhancing metalloprotease production, neovascularization, oxidative stress, cysteine sequestration, and arginine depletion, many of which require cell-to-cell contact within the TME. Specialized tertiary lymphoid structures within some tumors provide the platform for the cellular cross-talk that defines the set point between immu-nosuppressive and immunity-promoting TMEs, and are the focus of a review by Engelhard and coauthors (7). Under-standing the generation and function of these heterogeneous lymph node–like structures is a prerequisite for learning to manipulate the development of intratumoral tertiary lymphoid structures to promote T cell infiltration and the generation of antitumor responses in both primary and metastatic lesions. Multispectral immunofluorescence image depicting three tertiary lymphoid structures (TLS) in close proximity to a mouse melanoma metastasis that lacks immune infiltration. The image depicts CD8 1 (green), CD20