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Polyfunctional response by Imm TAC ( IMC gp100) redirected CD 8 + and CD 4 + T cells
Author(s) -
Boudousquie Caroline,
Bossi Giovanna,
Hurst Jacob M.,
Rygiel Karolina A.,
Jakobsen Bent K.,
Hassan Namir J.
Publication year - 2017
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12779
Subject(s) - cytotoxic t cell , t cell , cd8 , immune system , biology , cancer immunotherapy , chemokine , tumor necrosis factor alpha , interleukin 21 , microbiology and biotechnology , immunology , cancer research , immunotherapy , in vitro , biochemistry
Summary The success of immune system‐based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors ( TCR s) against cancer (Imm TAC ™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti‐ CD 3 scFv antibody) were previously shown to redirect CD 8 + and CD 4 + T cells against tumours. Here we present evidence that IMC gp100 (Imm TAC recognizing a peptide derived from the melanoma‐specific protein, gp100, presented by HLA ‐A*0201) efficiently redirects and activates effector and memory cells from both CD 8 + and CD 4 + repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD 8 + T cells redirected by IMC gp100 are potent killers of melanoma cells. Furthermore, CD 4 + effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMC gp100. The majority of T cell subsets belonging to both the CD 8 + and CD 4 + repertoires secrete key pro‐inflammatory cytokines (tumour necrosis factor‐ α , interferon‐ γ , interleukin‐6) and chemokines (macrophage inflammatory protein‐1 α ‐ β , interferon‐ γ ‐inducible protein‐10, monocyte chemoattractant protein‐1). At an individual cell level, IMC gp100‐redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti‐cancer response. This study demonstrates that IMC gp100 induces broad immune responses that extend beyond the induction of CD 8 + T cell‐mediated cytotoxicity. These findings are of particular importance because IMC gp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma.