CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti–PD-1 Treatment

Abstract

Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response. We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy. Increased numbers of CD69CD103 tumor-resident CD8 T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti-PD-1 immunotherapy. Tumor-resident CD8 T-cell numbers are more prognostic than total CD8 T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. .

Skin‐resident memory T cells as a potential new therapeutic target in vitiligo and melanoma

“…Tumor infiltration of CD8 + T cells exhibiting a resident phenotype (CD69 + CD103 + and/or CD103 + ) correlates with a more favorable prognosis for various human cancers (Djenidi et al, ; Koh et al, ; Wang et al, ; Webb, Milne, Watson, Deleeuw, & Nelson, ). Similar correlations were shown for human melanoma (Edwards et al, ; Murray et al, ) (Figure ). CD103 + CD8 + T cells, residing in the tumor microenvironment, were strongly correlated with increased melanoma‐specific survival in immunotherapy‐naïve stage III melanoma patients (Edwards et al, ).…”

Accumulation of CD103+ CD8+ T cells in a cutaneous melanoma micrometastasis

“…In the occult micrometastasis, we observed a prominent population of CD8 + CD103 + T cells in close proximity to SOX10 + melanoma cells, suggesting that human T RM cells can survey dormant melanoma cells and maintain immune equilibrium. This is in line with recent reports demonstrating the presence of CD103 + T RM in close proximity to tumor cells in patients with different types of cancers, including melanoma and breast cancer . Such results further echo our findings in mouse skin where T RM cells can directly interact with and control dormant melanoma microlesions .…”

“…Emerging clinical data further suggest that T RM cells provide immune surveillance in a variety of human cancers . Importantly, the density of T RM cells within the tumor environment has been shown to predict for improved survival in a number of cancer types, including advanced‐stage melanoma . In line with this, recent reports have shown that T RM cells afford potent antitumor immunity in mouse models .…”

“…Accordingly, the generation of large numbers of T RM cells in skin is associated with improved immune control and suppressed cancer progression. Several recent reports in a multitude of human cancers, including melanoma, suggest that T RM cells can promote immune surveillance and that their strong accumulation serves as a prognostic biomarker for improved clinical outcomes . However, those studies have focused on advanced and, most likely, immune‐escaped tumors.…”

Resident memory T cells, critical components in tumor immunology

“…Therefore, their exhausted phenotype does not preclude their sensitivity to reactivation and invigoration [95]. Consistently, recent results revealed expansion of T RM cells in melanoma patients responding to anti-PD-1 immunotherapy [96]. …”