Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

Koukourakis, Ioannis M; Gkegka, Anastasia G; Xanthopoulou, Erasmia; Nanos, Christos; Giatromanolaki, Alexandra; Koukourakis, Michael I.

doi:10.3390/curroncol29060342

Cited by 14 publications

(14 citation statements)

References 37 publications

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“…An important finding was also the association of HIF1α with low infiltration of PCs with TILs in accordance with previous studies in breast and head–neck cancer [ 27 , 28 ]. A hypoxic and acidic TME provides a functional barrier against cytotoxic lymphocytes, blocking their proliferation and cytotoxic activity, and furthermore, promotes regulatory T-cell and monocyte prevalence [ 6 – 10 ].…”

Section: Discussionsupporting

confidence: 91%

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer

et al. 2023

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PD-L1/PD-1 pathway is a major pathway exploited by human cancer types, which is a target for current immunotherapy. We investigated tumor microenvironmental factors involved in PD-L1 induction in prostate cancer (PC). We studied the expression of PD-L1 in a series of 66 PCs, in parallel with the expression of hypoxia- and acidity-related immunohistochemical markers (Hypoxia-inducible factor HIF1α, and lactate dehydrogenase LDHA) and tumor-infiltrating lymphocyte TIL density. Experiments with three PC cell lines, the 22Rv1, DU145, and PC3 were conducted focusing on the inducibility of PD-L1 by hypoxia, acidity, lymphocyte interactions, and radiation. In tissues, PD-L1 expression by cancer cells was directly related to PD-L1 expression by TILs and macrophages (p < 0.05), and the overexpression of HIF1α and LDH5 (p < 0.05). TIL density was inversely related to ΗΙF1α (p = 0.02). Exposure of PC cell lines to hypoxia strongly induced PD-L1 and protein and mRNA levels, directly controlled by HIF1α function (p < 0.001). Irradiation with 20 Gy had no apparent effect on PD-L1 expression. Culturing PC cell lines with culture medium (CM) from PBMCs strongly induced PD-L1 at protein and mRNA levels, independently from HIF1α, which was also confirmed when cells were incubated with Interferon-γ (p < 0.001). It is concluded that the combination of anti-PD-L1/PD-1 immunotherapy with hypoxia/HIF-targeting may be important in the treatment of specific subgroups of PC patients.

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Section: Discussionsupporting

confidence: 91%

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer

et al. 2023

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“…This points to the importance of obtaining a sample immediately prior to chemoradiation, when surgical debris has decreased. Moreover, while some postresection cfDNA may be attributable to debris, it remains to be established in gliomas whether post-resection cfDNA levels correlate with patient prognosis, as has been identified in other cancer types 43,44 .…”

Section: Discussionmentioning

confidence: 99%

Longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA: one patient at a time

Riviere-Cazaux,

Dong,

et al. 2024

Preprint

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IMPORTANCECurrent methods for glioma treatment response assessment are limited. Intracranial cerebrospinal fluid (CSF) may provide a previously untapped source of longitudinal biomarkers, such as cell-free DNA (cfDNA), for disease monitoring.OBJECTIVETo assess the feasibility of obtaining longitudinal intracranial CSF cfDNA from patients with gliomas during their disease course.DESIGNThis case series was initiated in 2021, with patients followed until last clinical follow-up (death or present time).SETTINGThis single-center study was conducted at a large academic medical center.PARTICIPANTSAdults with gliomas were recruited for longitudinal intracranial CSF collection using 1) Ommaya reservoirs, from which CSF would be sampled on at least two separate occasions, or 2) CSF collection from other clinically indicated CSF access devices, such as ventriculoperitoneal (VP) shunts.INTERVENTIONSCSF was collected from Ommaya reservoirs in four patients and from an existing VP shunt in one patient.MAIN OUTCOMES AND MEASURESThe study aimed to collect CSF for biobanking and biomarker discovery, with the hypothesis that CSF could serve as a source of longitudinally acquirable biomarkers.RESULTSFive patients (2 females, 3 males; median: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4/5 patients) or VP shunt (n=1/5). Three patients had glioblastoma and two had astrocytoma, IDH-mutant, grade 4. In total, thirty-five CSF samples were obtained (median: 3.80 mL; 0.5-5 mL), with 30 (85.7%) yielding sufficient cfDNA for Next-Generation Sequencing (n=28) or Low-Pass Whole Genome sequencing (all samples). Tumor fraction was found to increase with radiographic progression. Changes in variant allelic frequencies (VAFs) may be seen within individual patients after resection and chemoradiation. In two patients, changes in tumor-specific IDH1 VAF correlated with CSF D-2-hydroxyglutarate levels, the oncometabolite of IDH mutant tumors. Copy number burden (CNB) decreased below the limit of quantification during treatment.CONCLUSIONS AND RELEVANCELongitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Ongoing studies will evaluate hypotheses generated in this case series regarding how longitudinal CSF cfDNA could be utilized to sensitively detect changes in disease burden.Trial RegistrationNCT04692324https://clinicaltrials.gov/study/NCT04692324;NCT04692337https://clinicaltrials.gov/study/NCT04692337QUESTIONWhat is the feasibility of obtaining longitudinal intracranial cerebrospinal fluid cell-free DNA from patients with high-grade gliomas to evaluate changes during treatment?FINDINGIn this case series, we find that CSF cfDNA can feasibly be obtained throughout treatment via CSF access devices. We find that changes in tumor fraction or tumor-associated variant allele frequencies (VAFs) may correlate with disease trajectory, with VAFs positively correlating to other tumor-associated candidate biomarkers.MEANINGLongitudinal cerebrospinal cell-free DNA may inform the impact of treatment throughout a specific patient’s disease course, from the time of resection through radiographic progression.

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“…For instance, a study on head and neck cancer observed that the frequency of infiltrated TILs into the tumor site increased following radiotherapy and chemo/radiotherapy. Furthermore, this investigation reported that the expression of HIF-α as a hypoxia indicator decreased following the combination therapy ( 203 ).…”

Section: Combination Of Tils With Other Anti-cancer Therapiesmentioning

confidence: 97%

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

et al. 2022

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Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.

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Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

Cited by 14 publications

References 37 publications

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer

Longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA: one patient at a time

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

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