Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Abstract

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.

Keywords: Biomarker; Cancer immune phenotype; Cancer immune responsiveness (CIR); Germline molecular alterations; Immune checkpoint inhibitor (ICI); Immune oncology (IO); Immunogenic cell death (ICD); Immunotherapy; Somatic molecular alterations; Tumor microenvironment (TME); Tumor mutational burden (TMB).

Fig. 1

Germline contributions to CIR. Germline genetic contributions to CIR. Genetic germline variants can influence CIR in different ways, which are tightly interconnected. Variants associated with attitude to smoke or mutation in DNA-repair genes (e.g., DNA mismatch repair genes) can cause the accumulation of somatic alterations which in turn might facilitate the parallel development of neoepitope-mediated immune recognition.. Polymorphisms of genes that modulate critical immunologic pathways such as IFN signaling and differentiation and function of T cells and B cells might influence the development of tolerant vs cytotoxic TME. The same could be said of variants in genes governing antigen presentation such as HLA class I and II, ICD, innate-immunity function in macrophages, natural killer (NK) cells, and granulocytes. Polymorphisms of TLR4, P2RX7, and FPR1 have been associated with differential outcome in breast and colon cancer patients treated with adjuvant chemotherapy, likely through the modulation of ICD-mediated anti-tumor immune response [63, 64]. HLA-E, a non-classical HLA molecule, is recognized by specific NK cell lectin-type receptors with either activating or inhibiting activity in the context of specific and redundant antigenic presentation. HLA-E polymorphisms might have an impact on anti-tumor response independently from the CIR mechanisms recognized so far [65]. Variants in genes encoding for chemokines or chemokine receptors might also differentially modulate intra-tumoral recruitment of immune cells. Variations in protein-coding regions of genes affecting structure or expression of molecules targeted by IO agents might influence their efficacy. Polymorphisms of crystallizable fragment (Fc)-γ receptor genes have been associated, although inconsistently, with distinct outcomes in patients treated with Rituximab and Trastuzumab [66]. Such variations might potentially influence the efficacy ICIs via antibody-dependent cytotoxicity (ADCC) lysis of target or tumor cells [67]

Fig. 2

The tumor-immune microenvironment consists of a variety of cell types. All cell types comprise different transcriptional profiles. The top depicts all major categories of cell types present in a TME with a color code indicating their overall predictive value for immune responsiveness (red more responsive; blue less responsive). Some transcriptional alterations impacting immune responsiveness are highlighted beneath. The middle depicts a tumor and a subset of immune cells found within a TME and represents the challenge transcriptional profiling is facing right now. The bottom depicts the ultimate goal – using transcriptional profiling of whole tumor or single cells of the TME to predict immune responsiveness

Fig. 3

Immunogenic Cell Death (ICD) and Tolerogenic Cell Death (TCD). Immunogenic cell death can be induced by a variety of mechanisms that are still being defined, including low dose radiation, low dose chemotherapy, oncolytic viruses and others. ICD triggers translocation or release of DAMP factors from the dying cell in distinct spatiotemporal patterns that shape the subsequent immune response. DAMPs engage with receptors on antigen presenting cells (APCs) and, in combination with tumor-associated antigens and type I IFN, trigger APC activation, maturation, and trafficking to draining lymph nodes. This process can be augmented with TLR agonists in some instances. Once in the lymph node, APCs engage with cognate T cells and drive T cell activation and proliferation. T cells then traffic to the tumor via CXCL9/10/11 gradients induced by type I IFN signaling in tumor cells, which can result in rapid tumor elimination and generation of long term protective immune memory. In contrast, TCD including most forms of apoptosis is a non-inflammatory pathway for cell death which is characterized by membrane blebbing and loss of DAMP secretion, with sequestration of high-mobility group protein 1 (HMGB1) and phosphatidylserine exposure on the cell surface. Consequently, pro-inflammatory cytokines including IL-1 and TNF are not released to activate endothelium and recruit other T cells. Ectonucleotidases CD39 and CD73 degrade ICD-associated ATP to adenosine thereby inhibiting T and NK cell responses with expression of the A2A adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (Treg) and inhibits T cell effector function. An immunosuppressive environment characterized by enhanced myeloid derived suppressor cells and regulatory T cells is established while T cells fail to activate and form a productive immune response