Tumour radiosensitivity is associated with immune activation in solid tumours

Abstract

Purpose Our goal was to determine whether tumor radiosensitivity is associated with activation of the immune system across all tumor types as measured by two gene expression signatures (GES). Methods We identified 10,240 genomically profiled distinct solid primary tumors with gene expression analysis available from an institutional de-identified database. Two separate GES were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity), and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumor samples, and in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterized, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumor radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation. Results Using an RSI cut-point of ≤0.3745, RSI-low tumors (n=4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 [range −0.136,1.095]) compared with RSI-high tumors (−0.17 [−0.82,0.42]; p<0.001) across all tumor samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p=0.02), with RSI (HR 0.63 [95%CI 0.36,1.09]) and 12-CK (HR 0.66 [0.41,1.04]) each providing comparable contributions. Conclusions Tumor radiosensitivity is associated with immune activation as measured by two GES.

Identification and validation of single-sample breast cancer radiosensitivity gene expression predictors

“…More interestingly, the 10-GS could only be validated in ER-RT+ patients, and the ER + RT- tumors predicted as radioresistant actually had a lower risk of IBTR, which is consistent with the follow-up study by the original authors [ 16 ]. As the 10-GS is negatively correlated with proliferation and immune response, as was also shown recently by the original authors [ 17 ], this means that the tumors predicted as radioresistant were mainly slowly proliferating, and it therefore makes sense that ER+ tumors predicted as radioresistant have a better outcome. Further, the tumors predicted as radioresistant have a lower immune response, which may explain why ER- tumors predicted as radioresistant have a worse outcome, as the immune response is more important in highly proliferating and ER- tumors.…”

“…Indeed, this was shown when Torres-Roca et al presented the follow-up study of RSI in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) breast cancer, and only could validate previous findings in ER- tumors [ 16 ]. Interestingly, RSI was recently further shown to correlate with immune response genes, which may partly explain the subgroup-specific performance, as the immune response is more important for prognosis in ER- breast cancer [ 17 , 18 ].…”

Tertiary lymphoid structures in the era of cancer immunotherapy

“…A large array of data supports the idea that cancer therapies that stimulate antitumour immune responses are most effective at producing long-term responses 4,109 . Although self-evident for immunotherapies 27,110 , this concept has gained strength when also considering conventional chemotherapies 111 , radiation therapy 112,113 and targeted therapies 114 . With TLSs being a paramount characteristic of the immune contexture of tumours 109 , as they represent major sites where antitumour immune responses are generated 7,18 , it has become necessary to assess their impact on response to treatment and their modulation by therapies.…”

Hadron Therapy Based on Laser Acceleration in the Plasma Channel Using Oxygen Ionization

“…In-vitro models have been created to anticipate and investigate the tumor cell radiosensitivity. The cell radiosensitivity is relatively defined based on the dose deposited in tumors, which is represented as an exponential equation [41]. Dose delivery indicates a key issue in the full therapy process with Hadron therapy since it permits the change of the beam turning out from the accelerator into a clinical dose circulation, which should be conformed to the medicinal prescription [42].…”