Abstract
Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors.
Highlights
The revolution brought about by the advent of checkpoint inhibitors has changed the face of oncology, moving from cancer cell-centric investigation to immunocentered studies
The top 5 tumors most invaded by lymphoid cells were thymoma, testicular germ cell tumor, clear cell kidney cancer, non-small cell lung cancer (NSCLC) adenocarcinoma, and cervical cell carcinoma (Figure 1B), while the top 5 tumors most invaded by myeloid cells were cholangiocarcinoma, ovarian cancer, kidney renal clear cancer, NSCLC, and pancreatic adenocarcinoma (Figure 1C)
In the 4 cohorts, using the area under the curve (AUC), we found that the lymphoid score or tumor-infiltrating lymphocytes (TIL) score compared favorably to classical signatures such as expanded immune gene (EIG) or immune infiltrate, as evaluated by CD3E expression (Figure 5G–J)
Summary
The revolution brought about by the advent of checkpoint inhibitors has changed the face of oncology, moving from cancer cell-centric investigation to immunocentered studies. Innate and adaptive immune response may detect cancer cells. Cancers 2020, 12, 2418 present antigens to T-cells, which in turn migrate into the tumor to fight against tumor growth. There is a clear rational underpinning of the hypothesis that high-grade in situ immune response may be associated with better tumor control [1,2]. Many studies suggest that immune infiltrates with high densities of CD3 and CD8 T cells are associated with better outcomes [3]. Tumor-infiltrating lymphocytes (TIL) scored on hematoxylin and eosin slides (H&E) represent a standard tool for predicting cancer prognosis in breast cancer [6,7]
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