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Macrophage Derived CXCL9 and CXCL10 Are Required for Anti-Tumor Immune Responses Following Immune Checkpoint Blockade

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Macrophage Derived CXCL9 and CXCL10 Are Required for Anti-Tumor Immune Responses Following Immune Checkpoint Blockade Author Manuscript Published OnlineFirst on October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Macrophage-derived CXCL9 and CXCL10 are critically required for anti-tumor immune responses 2 following immune checkpoint blockade 3 Imran G. House1,2,+, Peter Savas2,3,+, Junyun Lai1,2, Amanda X.Y. Chen1,2, Amanda J. Oliver1,2, Zhi L. 4 Teo2,3, Kirsten L. Todd1,2 Melissa A. Henderson1,2, Lauren Giuffrida1,2, Emma V. Petley1,2, Kevin Sek1,2, 5 Sherly Mardiana1,2, Tuba N. Gide4, Camelia Quek4, Richard A. Scolyer4,5, Georgina V. Long4,6,7 James S. 6 Wilmott4, Sherene Loi2,3, Phillip K. Darcy1, 2, 8, 9* and Paul A. Beavis1,2* 7 1Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, 3000, Victoria, Australia. 8 2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia. 9 3Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, 10 Australia. 4The University of Sydney, Melanoma Institute Australia, Sydney, NSW, Australia. 5Royal 11 Prince Alfred Hospital, Sydney, NSW, Australia.6 Royal North Shore Hospital, Sydney, NSW, Australia. 12 7Mater Hospital, North Sydney, NSW, Australia. 8Department of Pathology, University of Melbourne, 13 Parkville. 9Department of Immunology, Monash University, Clayton. +Contributed equally, *Contributed 14 equally as senior authors. 15 Key words: cancer, anti-PD-1, anti-CTLA-4, CXCL9, CXCL10, CXCR3 16 Address correspondence and reprint requests to Paul A. Beavis ([email protected]) or Phillip K. 17 Darcy ([email protected]), Cancer Immunology Program, Peter MacCallum Cancer Centre, 18 Victoria, Australia. Telephone (613) 85595051 19 This work was funded by a Program Grant from the National Health and Medical Research Council 20 (NHMRC; Grant number 1132373) and a National Breast Cancer Foundation Grant (IIRS-19-016 19-22). 21 P. A. Beavis is supported by National Breast Cancer Foundation Fellowship (ID# ECF-17-005). P. K. 22 Darcy is supported by an NHMRC Senior Research Fellowship (APP1136680). 23 Conflict of interest: The authors declare no conflict of interest. 24 25 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 26 Statement of Translational Relevance 27 Treatment with immune checkpoint inhibitors has been highly successful in a subset of tumor types, 28 particularly those with increased levels of immune infiltrate. However, the mechanism and the immune 29 cell subsets critical for successful clinical responses are not fully understood. This study demonstrates that 30 the chemokines CXCL9/10 are indispensable for robust responses to immune checkpoint inhibitors (anti- 31 PD-1 and anti-CTLA-4) and, in particular, that CXCL9/10-secreting macrophages are critical for their 32 therapeutic efficacy. Moreover, we identified a novel transcriptional signature in macrophages that was 33 associated with positive patient responses to immune checkpoint inhibitors that was lacking in non- 34 responding patients. This is of significant interest to the field, challenging the paradigm that macrophages 35 are pro-tumoral and detrimental to anti-tumor immune responses through immunosuppressive 36 mechanisms, including expression of PD-L1. These findings indicate that the intratumoral macrophage 37 phenotype is a key feature in determining responses to immune checkpoint inhibitors that can be exploited 38 either diagnostically or therapeutically. 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 39 Abstract 40 Purpose: Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with 41 the extent of tumor immune infiltrate but the mechanisms underlying the recruitment of T cells following 42 therapy are poorly characterized. A greater understanding of these processes may see the development of 43 therapeutic interventions that enhance T cell recruitment and, consequently, improved patient outcomes. 44 We therefore investigated the chemokines essential for immune cell recruitment and subsequent 45 therapeutic efficacy of these immunotherapies. 46 Experimental design: The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using 47 nanosting-based analysis with results confirmed at the protein level by flow cytometry and cytometric 48 bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and 49 immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using 50 single-cell RNAseq and paired survival analyses. 51 Results: The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD- 52 1/CTLA-4 blockade and both CD8+ T cell infiltration and therapeutic efficacy were CXCR3 dependent. 53 In both murine models and patients undergoing immunotherapy, macrophages were the predominant 54 source of CXCL9 and their depletion abrogated CD8+ T cell infiltration and the therapeutic efficacy of 55 dual immune checkpoint blockade. Single cell RNA-seq analysis of patient TILs revealed that 56 CXCL9/10/11 was predominantly expressed by macrophages following ICB and we identified a distinct 57 macrophage signature that was associated with positive responses to immune checkpoint blockade. 58 Conclusions: These data underline the fundamental importance of macrophage-derived CXCR3 ligands 59 for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient 60 responses. 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 61 Introduction 62 Immunotherapy, and in particular immune checkpoint therapy, has emerged as a powerful treatment 63 strategy in several cancer types (1). Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1 and anti- 64 CTLA-4 used alone or in combination provide durable responses in a subset of patients. However, it is not 65 fully understood which parameters influence the likelihood of patient response (1, 2). Factors that have 66 been reported to predict responses to immune checkpoint inhibitors include the mutational load of the 67 tumor (3), the expression of target ligands such as PD-L1 and the presence of high number of TILs (4). It 68 is now clear that the number of CD8+ T cells at the tumor site is a strong predictor of response to anti-PD- 69 1 therapy in melanoma (4). However, a large proportion of patients exhibit an immune-exclusion or 70 immune-desert phenotype and a number of strategies are currently being developed to enhance immune 71 infiltrate in this patient subtype (5). The efficacy of immune checkpoint blockade depends upon the 72 recruitment of tumor-infiltrating lymphocytes and yet the mechanism by which this occurs is largely 73 unknown. Since the trafficking of immune cells, including T cells, is modulated by chemokine: chemokine 74 receptor interactions, this prompted us to evaluate the chemokine networks responsible for the recruitment 75 of T cells following immune checkpoint blockade. Chemokines interact with their respective chemokine 76 receptors and this binding leads to the activation of intracellular signaling pathways which result in the 77 migration of the target cells towards the source of the chemokine. T cells express a range of chemokine 78 receptors including CCR2, CCR4, CCR5 and CXCR3 which respond to a range of chemokines. In the 79 context of cancer, the ligands of CCR5 (CCL5) and CXCR3 (CXCL9, CXCL10 and CXCL11) have been 80 shown to associate with levels of TIL infiltrate in human cancers (6-8) and the production of CXCL9 and 81 CXCL10 has been associated with improved responses to chemotherapy (9-11) and adoptive cellular 82 therapy (12-14). CXCL11 binds to CXCR3 with the highest affinity, followed by CXCL10 and CXCL9 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 21, 2019; DOI: 10.1158/1078-0432.CCR-19-1868 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 83 (15, 16) and notably CXCL11 binds to the CXCR3 receptor at a distinct binding site of the receptor (17), 84 potentially leading to diverse signaling outcomes (18). 85 In the current study, an unbiased analysis of the maximally upregulated chemokines following dual PD- 86 1/CTLA-4 blockade revealed that CXCL9 and CXCL10 were significantly upregulated in the tumor 87 microenvironment following therapy. Neutralization of CXCR3, the receptor for CXCL9 and CXCL10, 88 abrogated the therapeutic efficacy of dual PD-1/CTLA-4 blockade and was associated with reduced 89 infiltration and activation phenotype of CD8+ T cells in the tumor and draining lymph
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