Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile

Abstract

Non-small cell lung cancer (NSCLC) is the second most prevalent type of cancer.With the current treatment regimens, the mortality rate remains high. Therefore, better therapeutic approaches are necessary. NSCLCs generally possess many genetic mutations and are well infiltrated by T cells (TIL), making TIL therapy an attractive option. Here we show that T cells from treatment naive, stage I-IVa NSCLC tumors can effectively be isolated and expanded, with similar efficiency as from normal lung tissue. Importantly, 76% (13/17) of tested TIL products isolates from NSCLC lesions exhibited clear reactivity against primary tumor digests, with 0.5%-30% of T cells producing the inflammatory cytokine Interferon (IFN)-γ. Both CD4 + and CD8 + T cells displayed tumor reactivity. The cytokine production correlated well with CD137 and CD40L expression. Furthermore, almost half (7/17) of the TIL products contained polyfunctional T cells that produced Tumor Necrosis Factor (TNF)-α and/or IL-2 in addition to IFN-γ, a hallmark of effective immune responses. Tumor-reactivity in the TIL products correlated with high percentages of CD103 + CD69 + CD8 + T cell infiltrates in the tumor lesions, with PD-1 hi CD4 + T cells, and with FoxP3 + CD25 + CD4 + regulatory T cell infiltrates, suggesting that the composition of T cell infiltrates may predict the level of tumor reactivity. In conclusion, the effective generation of tumor-reactive and polyfunctional TIL products implies that TIL therapy will be a successful treatment regimen for NSCLC patients.

mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells

“…To assess T cell functionality, we performed an intracellular cytokine staining on splenocytes obtained from mice after three immunizations. Polyfunctional CD8 T cells, which produce more than one cytokine simultaneously, are associated with better control of infectious diseases 22,23 and tumors [24][25][26] and accounted for approximately 11% of CD8 T cells for both optimal LNPs (Figures 2E and 2F). To assess whether the activity of the LNPs also extended to other antigens, mRNA encoding the MC38 colon carcinoma-derived neo-epitope Adpgk or the B16-F10-derived melanocyte differentiation antigen Trp-2 was mixed with TriMix and encapsulated in LNP36.…”

Toll‐like receptor‐2/7‐mediated T cell activation: An innate potential to augment CD8+ T cell cytokine production

“…In general, T cells are extracted from patients and expanded ex vivo. 123,133 Depending on the treatment protocol, T cells can be either infused directly 123 or are genetically engineered, 134 for instance to render T cells refractive to inhibitory signals, 135 or to redirect antigen specificity 135,136 prior to reinfusion. 135,137 One approach to enforce tumor recognition by T cells is by making use of chimeric antigen receptors, or CARs.…”

Polyfunctional pathogen-specific CD4+ T cells reside in the lungs and tumors of NSCLC patients

“…Pathogen-specific bystander CD4 + T cells with a residency phenotype also reside in tumors of NSCLC patients. In the last years, it has become evident that a large proportion of CD8 + and CD4 + TILs are not tumor-specific 21,37 . Furthermore, many patients fail to respond to immune checkpoint therapy or adoptive cell transfer regimens.…”