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.

Agnostic Evaluation of Ipilimumab and Nivolumab Association: A Metanalysis.

“…In particular, an interesting component of immunotherapy is the long-lasting tumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients bene t from immunotherapy, and efforts should focus on improving the e cacy of immunotherapy through the use of both combination or sequential approaches and predictive biomarkers of response and resistance 17 . The goal of combination approaches, targeting several steps of the cancer-immunity cycle, is to expand the spectrum of patients who respond to cancer immunotherapy (increased number of responding patients in tumors that are sensitive to single agent therapy and the identi cation of new sensitive tumor types that do not respond to monotherapy alone) and to improve the quality of clinical responses (i.e., time span of response, PFS and OS) beyond what can be achieved with monotherapy alone.…”

Germline genetic contribution to the immune landscape of cancer

“…Tumor-host interactions are important determinants of carcinogenesis and metastatic progression (Hanahan and Weinberg, 2011). The type and density of immune-cell infiltration in the tumor microenvironment are associated with differential prognosis (Bedognetti et al, 2019;Galon et al, 2006;Pagès et al, 2018). Metastases evolve in the context of selection by the immune system .…”

“…Tumor immune infiltration has been shown to predict responsiveness to immunotherapy (Tumeh et al, 2014). Therefore, advancing our understanding of the factors that underlie the host immune response to the tumor may help identify additional pathways to target for therapy (Bedognetti et al, 2019).…”

“…Environmental factors such as the microbiome may also modify the immune microenvironment and affect response to immunotherapy (Fessler et al, 2019). Host genetic factors have not been explored in depth as predictors of immune responsiveness (Bedognetti et al, 2019).…”

A MAP of tumor-host interactions in glioma at single cell resolution

“…The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms (Bedognetti et al, 2016; Joyce and Fearon, 2015; Zhang et al, 2019) and influences the response to immune therapies (Ceccarelli et al, 2016; Cristescu et al, 2018). Therefore, the elucidation of the tumor-host interaction mechanisms plays a crucial role in the understanding of the tumor growth and evolution (Angelova et al, 2018; Bedognetti et al, 2019) and for the identification immuno-oncology therapeutic targets (Hoos, 2016). Immune checkpoint inhibitor (ICI) therapies are aimed to targeting the specific cell-cell interaction between PD1 and PD-L1 or CTLA4 and B7-1/B7-2 (Pardoll, 2012).…”