Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy

Abstract

BackgroundRadiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.MethodsWe used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells.ResultsWe show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8+ T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor.ConclusionsThese correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.

Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

“…However, when both the tumor and the DLNs were irradiated, the abscopal response was reduced, and this was associated with a reduction in the number of tumor specific CD8 + T cells, as well as stem-like CD8 + T cells, in both irradiated and not-irradiated tumors. These data suggest that DLNs might mediate the abscopal response, and potentially serve as a pool of stem-like CD8 + T cells, which can expand and migrate to populate the tumor [ 43 ].…”

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment

“…RT, if used appropriately, has a potential to convert a TME into a immuno-stimulative environment that can aid local and distant radiation-induced immune-mediated anti-tumor response [ 118 ] and enhance response to immune checkpoint inhibitors [ 119 , 120 , 121 ]. RT can alter the tumor micro-niche by increasing neo-antigen shedding, increase PD-L1 expression, increase MHC class I expression, and reverse exhausted CD8+ T-cells [ 120 ].…”

Modeling Radioimmune Response—Current Status and Perspectives

“…Indeed it is evident that patients with lymphopenia have a worse therapy prognosis ( 12 – 17 ). Experimental studies indicate that (i) lymph node irradiation is a crucial factor that should be avoided, if possible ( 10 , 11 ), and that lymphocytes in general are quite radiosensitive and hence the blood pool is vulnerable by radiation ( 54 – 60 ). There are only few studies on the dose response of radiation induced lymphopenia ( 61 – 63 ), considering the dose distribution within the blood pool.…”