Volume 44, Issue 6, Pages 1255-1269 (June 2016) Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors  Jonathan M. Pitt, Marie Vétizou, Romain Daillère, María Paula Roberti, Takahiro Yamazaki, Bertrand Routy, Patricia Lepage, Ivo Gomperts Boneca, Mathias Chamaillard, Guido Kroemer, Laurence Zitvogel  Immunity  Volume 44, Issue 6, Pages 1255-1269 (June 2016) DOI: 10.1016/j.immuni.2016.06.001 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Major Factors Contributing to Primary Resistance to ICB Therapy Many potential tumor-related, host-related, and environmental factors can explain the degree of heterogeneity seen with ICB immunotherapies. These can be categorized into influences from the tumor microenvironment, endocrine and metabolic factors, environmental factors, and other influences such as age and unfavorable host genetics. Immunity 2016 44, 1255-1269DOI: (10.1016/j.immuni.2016.06.001) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Immune-Checkpoint Blockade Mobilizes the Gut Microbiota to Promote Anti-tumor Immune Responses Uptake of distinct bacterial species (e.g., Bacteroides fragilis and Bifidobacteria) or bacteria-derived products by DCs in the context of ICBs can significantly enhance DC antigen-processing and -presentation functions (i.e., upregulation of costimulatory molecules and antigen-presentation molecules such as CD40 and MHC class II) and ensure DC production of cytokines such as IL-12. Together, this DC activation increases the generation of anti-tumor T cells and increases intratumoral T cell numbers. Alterations in the composition of the gut microbiota can affect host anti-cancer immunity. Blockade of CTLA-4 has also been found to modulate the microbiota composition and the function and integrity of the intestinal mucosal barrier, which could facilitate the immune-mediated therapeutic efficacy of anti-CTLA-4 mAb immunotherapy. Abbreviations are as follows: ICB, immune-checkpoint blockade; CTL, cytotoxic T lymphocyte; Th, T helper; DC, dendritic cell; IEL, intestinal epithelial lymphocyte; IEC, intestinal epithelial cell; IFN, interferon; and IL, interleukin. Immunity 2016 44, 1255-1269DOI: (10.1016/j.immuni.2016.06.001) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Mobilizing the Gut Microbiota to Circumvent Primary Resistance to ICB in Patients Determining the precise microbiome of a given patient is becoming possible with the development of metagenomics, metatranscriptomics, and culturomics platforms. The gathered information from these techniques can be used for selecting an approach that will facilitate a particular cancer immunotherapy. Ancillary therapeutic approaches that can be selected to achieve this might include probiotic formulations, gene products, products containing MAMPs, DIPs, mucosal vaccines, or potentially commensal antigens with molecular mimicry to tumor antigens. Immunity 2016 44, 1255-1269DOI: (10.1016/j.immuni.2016.06.001) Copyright © 2016 Elsevier Inc. Terms and Conditions