The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors

Abstract

Cancer immunotherapy with antibodies targeting immune checkpoints such as the PD-1/PD-L1 pathway have emerged as breakthrough treatment for multiple solid tumors with high response rates and durable remissions. Despite the benefit for patients and encouraging safety profile, severe inflammatory reactions are observed in some patients. Such immune-related adverse events (irAEs) frequently lead to temporary or permanent cessation of the treatment and require systemic immunosuppression yet underlying mechanisms of irAEs are not known in detail. Here, we describe the T cell-mediated immune reaction in irAE lesions of four patients that developed pneumonitis during therapy with a PD-1 blocking antibody. Immunohistochemical analysis was performed to map the environment of the inflammatory lesions. Tumor infiltrating T cell clones were identified by sequencing the T cell receptor, and comparison with clones from peripheral blood or secondary lymphoid organs. A significant overlap of clones infiltrating irAE lesions and tumors was found. The most prevalent clones were also expanded in peripheral blood, but only a minor fraction of clonal overlap was found. Our findings suggest that irAE lesions in patients under PD-1 blockade are infiltrated by T cells with similar specificity as tumor-infiltrating T cells. These results raise the possibility that the immune response is elicited in these patients against antigens shared by the tumor and distant organs affected by irAEs.

Managing immune dysregulation resulting from immune checkpoint inhibitors: impact of the ASCO guidelines and key take-homes for immunologists

“…In a report of two patients who died of myocarditis after receiving ipilimumab and nivolumab, similar T cell clones were found in the tumor (melanoma), skeletal muscles, and myocardium from one of the patients [8]. Consistent with this observation is a report of another study of four cases of pneumonitis in patients treated with ICI showing that the TCR repertoires in inflamed lung lesions and tumors overlapped significantly [9]. These observations suggest that cross-reactive T cells against a tumor and a related antigen in normal tissue might be involved in irAE pathogenesis [10].…”

Immune checkpoint inhibitor‐associated interstitial lung diseases correlate with better prognosis in patients with advanced non‐small‐cell lung cancer

“…Laubli et al . also revealed a similarity between T cells in irAEs lesions and tumor infiltrating lymphocytes (TILs) . These findings suggest that ILD reflects the infiltration of T cells with a specificity similar to tumor‐infiltrating T cells.…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…359 Beyond these nanotechnology-oriented studies, most of the other translational studies on ICD-inducing chemotherapies published over the past 2 years focused on combining ICD induction with immunotherapy or targeted anticancer agents, in keeping with current clinical trends. 360 D'Amico et al (University of Basel, Basel, Switzerland) found that an antibody specific for Erb-B2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) conjugated to an anthracycline derivate exerts potent anticancer effects that depend on cytotoxic T cells in a ERBB2-expressing syngeneic breast cancer model resistant to standard anti-ERBB2 therapy, and that this therapeutic effect can be further enhanced by PD-1 blockage. 205 Fend and collaborators (Gustave Roussy Cancer Campus, Villejuif, France) reported that an engineered oncolytic vaccinia virus, VV WR -TK − RR -Fcu1, can mediate ICD-dependent therapeutic effects (as documented by type I IFN signaling, increased CD8 + T cell infiltration, and improved ratio of effector CD4 + T cells to T REG cells in the tumor microenvironment) that can be potentiated by ICD-inducing chemotherapeutics or immune checkpoint blockers (ICBs).…”