“…Draining lymphatics house the majority of the tumor specific T cells, a site where DCs prime and expand antigen specific T cells, and where central memory is generated 17 . DLNs are also critical for the presence of an abscopal effect 30 and radiation of lymph nodes, more so than circulating blood, has been shown to drive radiation induced lymphopenia 31 . And yet current standard of care calls for comprehensive elective nodal targeting with surgery and/or radiation 6 .…”
In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer.
“…Draining lymphatics house the majority of the tumor specific T cells, a site where DCs prime and expand antigen specific T cells, and where central memory is generated 17 . DLNs are also critical for the presence of an abscopal effect 30 and radiation of lymph nodes, more so than circulating blood, has been shown to drive radiation induced lymphopenia 31 . And yet current standard of care calls for comprehensive elective nodal targeting with surgery and/or radiation 6 .…”
In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer.
“…On day 6 after tumor cell injection (when tumors reached an average size of 80 mm 3 ; henceforth defined as day 0 relative to tumor IR), 80% of the mice were positive for tumor cells in the axillary, brachial and/or inguinal lymph nodes (Fig. 1A–C ), which we previously identified as the DLNs of this region using Evans Blue dye 27 . Fig.…”
Section: Resultsmentioning
confidence: 93%
“…Interestingly, a modest increase in γH2AX positivity of the sham-irradiated NDLNs could be visually correlated with an increase in the irradiated volume. We previously demonstrated that even very small, tumor-only directed treatment fields significantly affect circulating lymphocytes 27 . Thus, the apparent increase in γH2AX positivity of sham-irradiated NDLNs could be due to IR-induced damage in the circulating lymphocytes which pass through the treatment fields during IR.…”
Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy to overcome immune evasion and to improve treatment response. However, clinical benefits of radiotherapy-immunotherapy combinations have been modest. Routine concomitant tumor-draining lymph node irradiation (DLN IR) might be the culprit. As crucial sites for generating anti-tumor immunity, DLNs are indispensable for the in situ vaccination effect of radiotherapy. Simultaneously, DLN sparing is often not feasible due to metastatic spread. Using murine models of metastatic disease in female mice, here we demonstrate that delayed (adjuvant), but not neoadjuvant, DLN IR overcomes the detrimental effect of concomitant DLN IR on the efficacy of radio-immunotherapy. Moreover, we identify IR-induced disruption of the CCR7-CCL19/CCL21 homing axis as a key mechanism for the detrimental effect of DLN IR. Our study proposes delayed DLN IR as a strategy to maximize the efficacy of radio-immunotherapy across different tumor types and disease stages.
“…For splenic irradiation there was no significant difference between CD8+ and CD4+. Radio-resistance of splenic lymphocytes compared to circulating lymphocytes has also been shown in a C57BL/6J mouse model after studying partial body irradiation with and without lymph node involvement (139). The authors also investigated the effect of different field sizes using a small animal image-guided irradiation device.…”
Section: Lymphocyte Radiosensitivity Studies In Micementioning
It is well known that radiation therapy causes lymphopenia in patients and that this is correlated with a negative outcome. The mechanism is not well understood because radiation can have both immunostimulatory and immunosuppressive effects. How tumor dose conformation, dose fractionation, and selective lymph node irradiation in radiation therapy does affect lymphopenia and immune response is an active area of research. In addition, understanding the impact of radiation on the immune system is important for the design and interpretation of clinical trials combining radiation with immune checkpoint inhibitors, both in terms of radiation dose and treatment schedules. Although only a few percent of the total lymphocyte population are circulating, it has been speculated that their increased radiosensitivity may contribute to, or even be the primary cause of, lymphopenia. This review summarizes published data on lymphocyte radiosensitivity based on human, small animal, and in vitro studies. The data indicate differences in radiosensitivity among lymphocyte subpopulations that affect their relative contribution and thus the dynamics of the immune response. In general, B cells appear to be more radiosensitive than T cells and NK cells appear to be the most resistant. However, the reported dose-response data suggest that in the context of lymphopenia in patients, aspects other than cell death must also be considered. Not only absolute lymphocyte counts, but also lymphocyte diversity and activity are likely to be affected by radiation. Taken together, the reviewed data suggest that it is unlikely that radiation-induced cell death in lymphocytes is the sole factor in radiation-induced lymphopenia.
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