Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma

Abstract

BackgroundDespite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes.MethodsWe bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect.ResultsThrough our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to ‘prime’ T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to ‘modulate the stroma’. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect.ConclusionOur data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

Hypofractionated Low-Dose Radiotherapy Combined with Immune Checkpoint Inhibition in Metastatic Solid Tumors

“…Low-dose radiation could favor M1 macrophage polarization, enhance NK cell infiltration, and reduce TGF-β, resulting in the promotion of the antitumor outcomes. 27 Yin et al got the same result. 38 At present, it is not clear whether different radiotherapy fraction modes can achieve the same bioequivalent dose, and whether the different fraction modes in animal experiments have the same effect as the conventional fraction and hypofraction in the clinical application.…”

How Macrophages Become Transcriptionally Dysregulated: A Hidden Impact of Antitumor Therapy

“…It is worth noting that STAT3 signaling also promotes cell survival after irradiation exposure via induction of anti-apoptotic proteins (survivin and Bcl-2), and this effect is more profound for M2-like TAMs [ 158 , 160 , 190 ]. The low radiation doses show a bidirectional impact on the anti-inflammatory TFs, comprised of STAT3 stimulation, as mentioned earlier, and STAT6 suppression with high IL-5 and 13 and low TGF-β cytokine profile [ 150 , 156 ]. Considering that NF-κB is also suppressed upon low-dose radiotherapy, macrophages may finally acquire anti-inflammatory characteristics, although this has to be further studied.…”

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

“…(ii) Would treatment to a proportion of the tumor with a high dose and other areas with a lower dose enhance immune cell infiltration? (iii) Would the omission of RT from a part of the tumor still result in sufficient antigen release and/or more favorable immune effect changes in the TME, with recruitment of T cells (so called ‘RadScopal’ effect) ( Figure 2 C) to generate a more effective systemic anti-tumor immune response [ 51 ]?…”

“…The ‘RadScopal’ effect arises as a consequence of radiation directed to part of the primary tumor, and may be accompanied by low-dose RT towards secondary lesions. It has been proposed that this double form of radiation, combined with ICIs, might be able to modulate the TME of both primary and secondary tumors, maximizing the anti-tumor immune responses [ 51 ]. Barsoumian et al investigated the priming of T cells in the Lewis lung carcinoma (LLC) mouse model using high-dose RT to a higher tumor burden.…”

“…These data suggest that low-dose RT can reprogram the TME, improve the infiltration and function of effector immune cells in the secondary tumors, and are able to overcome the inhibitory effects of the tumor stroma. Finally, the combination with the two ICIs could further increase and prolong the systemic effects of RT, via T regs blocking and attenuation of T cell exhaustion [ 51 ].…”