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.
Highlights
Tumor immunotherapy has changed the therapeutic landscape for patients with cancer
To date, established experimental systems have been flawed in answering this critical question because they cannot adequately replicate the complicated evolutionary processes inherently impacting human cancers in immune competent hosts
The taskforce was launched by a workshop held in San Francisco on May 14–15, 2018 that convened immunologists, geneticists, cell biologists, molecular biologists, biophysicists, computational analysts and oncologists, and aimed at two preeminent goals: 1) to identify the fundamental questions related to Cancer Immune Responsiveness (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 answer the fundamental questions and uncover mechanisms of CIR
Summary
Tumor immunotherapy has changed the therapeutic landscape for patients with cancer. While several classes of drugs are demonstrating clinical benefit, immune checkpoint inhibitor (ICI) therapy in particular has received considerable attention because these agents improve overall survival and are effective in a wide range of tumor types [1, 2]. Understanding common tumor-intrinsic features inhibiting anti-tumor immunity across cancers might be informative for the identification of broadly applicable tumor cell-intrinsic signatures mediating resistance These tumor-intrinsic factors can serve as both predictive and prognostic biomarkers that may improve patient selection, therapeutic decisions, and the identification of rational co-targets for more effective immunotherapy-based combinations. Immune-related cancer cell-intrinsic transcriptional alterations Alterations in expression of genes associated with tumor-immune recognition have been primarily associated with both innate and acquired resistance to immunotherapy These alterations mainly include deficiencies in antigenpresentation machinery and the IFN-γ response pathway [102, 135–137]. This integrated analysis would empower conclusions drawn from transcriptional analyses and would further increase its ultimate predictive value To complete this integrative approach, a major undertaking to generate databases is needed to correlate the transcriptional profiles (and other patient specific information) with clinical response to immunotherapy including immune-checkpoint blockade. Context dependent models will be able to dissect this question satisfactorily and, the two
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