International Journal of Radiation Oncology*Biology*Physics
Biology ContributionKinetics of Intratumoral Immune Cell Activation During Chemoradiation for Cervical Cancer
Introduction
Cervical cancer is among the most common malignancies among female patients worldwide, with an annual incidence of more than 500,000 women and an annual death rate of more than 250,000 women. (1) Locally advanced cervical cancer can be treated effectively with chemoradiation therapy (CRT) over a 7-week course of treatment requiring daily external beam radiation followed by brachytherapy (2); however, the rate of response to treatment is highly variable. 3, 4 Rapid responders to CRT are more likely to remain free of disease in the long term, but the mechanisms that underlie this heterogeneity in response rates are not well understood. Historically, radiation therapy (RT) was considered to have immunosuppressive effects; lymphocytes are one of the most radiosensitive cell types, (5) and peripheral lymphocyte counts generally decrease through the course of pelvic radiation. (6) More recently, radiation has been shown to uncover tumor antigens through tumor cell death, which enhances antigen presentation and induces antitumor T-cell responses. (7) Furthermore, radiation increases the release of damage associated molecular patterns, which attract and activate cells of the innate and adaptive immune system. (8)
Because of the challenges of obtaining frequent biopsies during RT, studies of immune activation are based on animal models using hypofractionated regimens, clinical studies with evaluation of tumors at very limited time points, or a focus on peripheral immune responses. As a result, the kinetics of intratumoral immune activation during RT are poorly understood. To discern the sequential changes within the cervix tumor microenvironment during CRT, we adapted the cytobrush methodology, demonstrated to be a reliable and minimally invasive technique to characterize immune cells within the female genital tract of HIV-positive patients in a multicenter clinical trial. (9) We recently reported the utility of this methodology for monitoring CD4 T cells at multiple mucosal tissues after intranasal vaccination in rhesus macaques. (10) By using this minimally invasive method, we characterized the immune infiltrate with multispectral flow cytometry at baseline and at weeks 1, 3, and 5 of CRT. Because T-cell infiltration has been associated with better prognosis in patients with cervical cancer and myeloid cells are known to modulate this infiltration, we focused our analysis on these populations. (11)
Section snippets
Patient population
Between January 2016 and January 2018, 20 patients were enrolled in a prospective observational clinical trial at MD Anderson Cancer Center and Lyndon B. Johnson Hospital designed to evaluate immunologic and metagenomic changes in the cervical and intestinal microbiota during CRT. Institutional review board approval was obtained, and all participants provided informed consent before enrolling in the study. Inclusion criteria and treatment are available in Methods E1 (available online at 10.1016/j.ijrobp.2018.06.404
Patient and tumor characteristics
Twenty patients with locally advanced cervical cancer (stage IBI-IIIB) were enrolled (Table E1; available online at https://doi.org/10.1016/j.ijrobp.2018.06.404). All patients completed treatment with external beam radiation with concurrent weekly cisplatin followed by pulsed-dose-rate or high-dose-rate brachytherapy.
T cells are transiently decreased after CRT followed by expansion in the cervical tumor
Cervical brushes were collected from visible tumors in patients; for patients with tumors that were not visible at week 5, the treated tumor site was brushed. On average, the yield
Discussion
The kinetics of immune activation within the local tumor microenvironment during CRT has not been well investigated because of challenges in obtaining serial biopsies during treatment. To our knowledge, this is the first study to evaluate the kinetics of changes in intratumoral immune cell subsets and their activation status during CRT.
We found that CRT induces an early and transient decrease of T cells during the first week of treatment. The percentage of activated CD69+ T cells increased
References (24)
- et al.
Therapy of human papillomavirus-related disease
Vaccine
(2012) - et al.
Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging
Int J Radiat Oncol Biol Phys
(2002) - et al.
Scent of dying cells: The role of attraction signals in the clearance of apoptotic cells and its immunological consequences
Autoimmun Rev
(2010) - et al.
Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells
Blood
(2009) - et al.
Innate immunity and the sensing of infection, damage and danger in the female genital tract
J Reprod Immunol
(2017) - et al.
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
Int J Cancer
(2015) - et al.
Predicting outcomes in cervical cancer: A kinetic model of tumor regression during radiation therapy
Cancer Res
(2010) - et al.
The long term effects of radiation of T and B lymphocytes in the peripheral blood after regional irradiation
Cancer
(1977) - et al.
Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation
J Immunol
(2014) - et al.
Radiation as an immunological adjuvant: Current evidence on dose and fractionation
Front Oncol
(2012)
Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility
J Immunol
Minimally invasive monitoring of CD4 T cells at multiple mucosal tissues after intranasal vaccination in rhesus macaques
PLoS One
Cited by (36)
Circulating neutrophils and tumor-associated myeloid cells function as a powerful biomarker for response to chemoradiation in locally advanced cervical cancer
2023, Clinical and Translational Radiation OncologyChemotherapy to potentiate the radiation-induced immune response
2023, International Review of Cell and Molecular BiologyPre-treatment immune status predicts disease control in NSCLCs treated with chemoradiation and durvalumab
2022, Radiotherapy and OncologyCitation Excerpt :Clinical studies have also found the drop in ALC due to RT to be more reflective of changes in peripheral B-cells rather than in T-cells [17]. Additionally, prospective evaluation of cervical cancer patients undergoing cCRT has found expansion of cytotoxic T-cells in the tumor microenvironment during cCRT despite a decreasing peripheral blood ALC [18]. Therefore, decreases in the peripheral ALC count do not necessarily equate functional immunosuppression, and the ALC may moreover be too crude of a measure.
Development of oncolytic viruses for cancer therapy
2021, Translational ResearchCitation Excerpt :Radiation causes DNA damage and cell death primarily through apoptosis.153 Apoptosis of the cancer cells was found to release tumor antigens and DAMPs which led to the activation of the immune system.154 Combinatorial therapy between OVs and radiation was reported to have a synergistic antitumor role in preclinical models by improving apoptosis.155,156
Prognostic and therapeutic TILs of cervical cancer—Current advances and future perspectives
2021, Molecular Therapy Oncolytics
J.K.S. and A.K. contributed equally to this study.
This study was funded by The University of Texas MD Anderson Cancer Center HPV-related Cancers Moonshot. The Flow Cytometry Core at MD Anderson Cancer Center is supported by the Cancer Center Support Grant NCI# P30 CA16672.
Conflict of interest: J.W. reports being a Healios cofounder, a MolecularMatch cofounder, a MolecularMatch officer, an OncoResponse cofounder/SAB, on the Reflexion Medical Scientific Advisor Board, on the Checkmate Pharmaceuticals Scientific Advisor Board, and on the Mavu Scientific Advisory Board. J.W. also reports BMS Clinical research support, Merck Clinical research support, Varian Laboratory research support, Incyte Laboratory research support, Merck Laboratory research support, Calithera Laboratory research support, Checkmate Pharmaceuticals Laboratory research support, and OncoResponse Laboratory research support. L.L.L reports an investigator-initiated study that is supported by AstraZeneca.