Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling

TY - JOUR

T1 - Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling

AU - Donia, Marco

AU - Harbst, Katja

AU - van Buuren, Marit

AU - Kvistborg, Pia

AU - Lindberg, Mattias F

AU - Andersen, Rikke

AU - Idorn, Manja

AU - Munir Ahmad, Shamaila

AU - Ellebæk, Eva

AU - Mueller, Anja

AU - Fagone, Paolo

AU - Nicoletti, Ferdinando

AU - Libra, Massimo

AU - Lauss, Martin

AU - Hadrup, Sine Reker

AU - Schmidt, Henrik

AU - Andersen, Mads Hald

AU - Thor Straten, Per

AU - Nilsson, Jonas A

AU - Schumacher, Ton N

AU - Seliger, Barbara

AU - Jönsson, Göran

AU - Svane, Inge Marie

N1 - ©2017 American Association for Cancer Research.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8þ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.

AB - Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8þ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.

KW - Journal Article

U2 - 10.1158/0008-5472.can-16-3172

DO - 10.1158/0008-5472.can-16-3172

M3 - Journal article

C2 - 28655789

SN - 0008-5472

VL - 77

SP - 4562

EP - 4566

JO - Cancer Research

JF - Cancer Research

IS - 17

ER -