Pai et al. demonstrated in a TRAMP-C2 model that combination anti-CTLA-4 + anti-PD-1 controlled tumor growth in a high tumor burden (HTB), but not in a low tumor burden (LTB) state. Although T cells were less exhausted in LTB than in HTB, the combination therapy led to apoptosis of the dominant tumor antigen-specific T cells by activation-induced cell death via high IFNγ expression in LTB, which also limited effector memory formation. Patients with LTB advanced melanoma had lower response rates with combination therapy than with anti-PD-1 alone. These results suggest that response to combination therapy may vary by disease context.
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-gamma (IFN-gamma) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-gamma production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-gamma secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
Author Info: (1) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of Cal
Author Info: (1) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (3) AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA. (4) AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA. (5) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (8) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (10) AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA. (11) Department of Hematopathology, School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (12) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (13) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (14) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (15) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (16) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (17) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (18) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (19) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (20) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (21) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (22) Girihlet, 355 30th Street, Oakland, CA 94609, USA. (23) Girihlet, 355 30th Street, Oakland, CA 94609, USA. (24) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (25) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (26) AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA. (27) Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: lawrence.fong@ucsf.edu.
