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TILs as Immune-oncology Markers in Routine Practice

Dr Amrit Kaur Kaler

The Programmed Cell Death or PD-L1 and Tumour-infiltrating Lymphocytes or TILs are emerging as biomarkers, says Dr Amrit Kaur Kaler, MD, who is a professor of Pathology at TOMCH. Also, she is a Fellow, Molecular Pathology and Cancer Genomics at Strand Life Sciences, HCG, Bengaluru.

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The Programmed Cell Death (PDL1) expression on the surface of tumour cells has emerged as a potential biomarker for predicting responses to immune checkpoint inhibitors (pembrolizumab) and prognosis in cancers like breast, prostate, lung, head and neck, etc. Cancer cells harbour Double Strand Breaks (DSB) after partial DNA Damage Repair (DDR) which alters tumour immunogenicity, lead to the transcription of altered proteins and might result in the formation of immunogenic neoantigens (neo-Ags). These neo-Ags elicit the antitumoral or a pro tumour response from the host immune system; the response can be mediated by cells from both the innate and adaptive immunity.

The innate immune response includes the recruitment of CD8 CTLs, NK cells (antibody dependant cell mediated cytotoxicity), macrophages M1, Th1 cells, DCs, and neutrophils. The adaptive immune response that rises against neo-Ags presented by the antigen presentation by the Human Leukocyte Antigen (HLA) molecules and that consists of Tand B-lymphocyte recruitment and activation. The tumour cells prevent the evasion of T regulatory cells by inducing the expression of “don’t eat me signals”, such as CD47, CD73, and PD-L1, regulated by the Hypoxiainducible Factor 1a (HIF 1a).

PD-1 is commonly expressed on these regulatory T cells, gets eliminated after its interaction with PD-L1 expressed on tumour cells; thus, letting tumour cells escape immune surveillance due to its inhibition on immune cell activation. The role of Immune Checkpoint Inhibitors (ICBs) is developed to target inhibitory checkpoint molecules (PDL-1) on tumour cells. The immunohistochemistry assessment of PD-1/PD-L1 expression >1% is being used as cut off for the use of Atezolizumab in metastatic triple-negative breast cancers with neoadjuvant chemotherapy which has shown increased pathologic Complete Response (PCR) rate and prolonged Progression-free survival Rate (PFS). Ipilimumab, a monoclonal antibody against human T cell protein CTLA-4 also induces long-term protection against cancer relapse.

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Other emerging biomarkers which have shown to benefit from ICB are the presence of a high extent of Tumour-infiltrating Lymphocytes (TILs) in tissue biopsies, the expression of immune gene signatures like Tumour Mutational Burden (TMB), circulating biomarkers like Lactate Dehydrogenase (LDH). TILs reflect a pre-existing baseline antitumor immune response and high TIL is associated with improved survival and with better responses to standard treatments

The morphological evaluation of TILs is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs can be classified as intratumoral (itTIL), lymphocytes localized in tumour nests having direct cellto-cell contact, and stromal (sTIL), present in the stroma between tumour cells. Techniques like immunohistochemistry (IHC) have been used to further investigate TIL composition and organization in the tumour tissue. Depending on the type and phenotype of the infiltrating immune cells (CD20, CD3, CD 16, CD57, foxp3) an antitumor immune response may be elicited, which might be favourable to the patient.

Cancer is a heterogeneous disease. Although IHC has proved to be useful in identifying few targets, next generation sequencing technology has facilitated identifying potentially actionable targets, which have been translated into daily clinical practice of treatment of cancer patients with monoclonal targetable therapies.

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