Chiffelle et al. showed that responders (Rs) to TIL therapy exhibited a greater number of CD8+ tumor-reactive T cells within tumor samples and in ACT products, while non-responders (NRs) were more likely to contain blood-borne clonotypes, mostly CD4+ T cells. Strikingly, R’s products contained 15-fold more reactive clonotypes than NR’s. TILs in Rs were primarily of a progenitor exhausted or terminal exhausted phenotype, while TILs in NRs were more EM-like. Upon expansion, cells from both Rs and NRs converged upon an effector-like phenotype. After ACT, R’s (but not NR’s) TILs acquired hallmarks of both immune activation (TCR and IFN signaling) and exhaustion (PD1, TOX).
Contributed by Morgan Janes
ABSTRACT: Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8(+) cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.
Author Info: (1) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Cent
Author Info: (1) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (2) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (3) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (4) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (5) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (6) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (7) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (8) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (9) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (10) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (11) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (12) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (13) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (14) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (15) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (16) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (17) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (18) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (19) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (20) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (21) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (22) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (23) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland; Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (24) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (25) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (26) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (27) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (28) Faculty of Nursing, National and Kapodistrian University of Athens, Athens, Greece. (29) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (30) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (31) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (32) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Electronic address: alexandre.harari@chuv.ch. (33) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: george.coukos@chuv.ch.
