Immune checkpoint inhibitors have recently gained popularity owing to their efficacy and low toxicity (1). Immunotherapy, in combination with conventional oncology treatment, can activate the body's autoimmune response to recognize tumor cells throughout the body (2). Radiotherapy has classically been considered a form of local treatment, causing direct damage to DNA in tumor cells. Because some immune cells are inherently sensitive to radiotherapy, radiotherapy also has both immunosuppressive and immunostimulatory activities (3). Combinations of local radiotherapy and systemic immunotherapy have been shown recently to have significant advantages in preclinical and clinical studies (4). Some studies have also confirmed that radiotherapy combined with immunotherapy can produce abscopal effects and perhaps what we term a “radio-memory” effect such that the addition of one to the other has synergistic effects (5, 6). Although radiation-induced abscopal effects have been reported in many studies (7–10), little is known about the radio-memory effect.

In terms of immunostimulatory effects, localized radiotherapy can stimulate systemic immune responses (3) by promoting the expression of tumor-associated antigens and the production of new tumor antigens to activate antitumor immune responses, counteracting the tumor's ability to inhibit antigen presentation. For instance, MHC-1, a key antigen recognized by CD8+ T cells, is significantly reduced in tumor cells (11). Radiotherapy can effectively promote the expression of MHC-1, promote the maturation of dendritic cells, and infiltrate tumors (12); reduce the numbers of Tregulatory cells (Tregs) in tumors; expand T-cell lineages; and enhance T cell migration. Radiotherapy has also been shown to partially or in some cases completely convert non-immunogenic tumors into immunogenic tumors (13). Radiotherapy in combination with anti-PD1/PDL1 antibodies, anti-CTLA4 antibodies, immune cytokines, dendritic cell vaccines, and Toll-like receptor antagonists can control local tumor progression, thereby improving overall survival (OS) and inducing specific immune responses to cancer (14).

The KEYNOTE-001 and PACIFIC studies confirmed that having had radiotherapy followed by treatment with a PD1/PDL1 inhibitor could produce a memory-specific immune anti-cancer effect (14, 15). We postulate that this result results from radiotherapy acting as a catalyst or ignition agent that may change a patient's overall immune microenvironment; radiotherapy may enhance the production and storage of immune memory cells, which when followed by immunotherapy would amplify the efficacy of the immunotherapy. With the above hypothesis, we evaluated the effects of intrapleural infusion of IL-2 for the treatment of malignant pleural effusions (MPE) caused by lung cancer, particularly whether these effects varied in patients who had received radiotherapy vs. in those who had not. Specifically, we sought to determine whether the radio-memory effect could occur after radiotherapy combined with other immunotherapy agents, or whether this effect is restricted to anti-PD1/PDL1 drugs.

Preclinical and clinical studies have shown that radiotherapy can enhance antitumor immune responses. A secondary analysis of the KEYNOTE-001 phase 1 trial, in particular, suggested that previous radiotherapy may improve the outcomes of patients given pembrolizumab relative to those for patients not given radiotherapy. Here we sought to determine whether radiotherapy combined with another well-known immune agent would produce similar radio-memory effect. In our retrospective analysis of outcomes among patients given intrapleural IL-2 or cisplatin for MPE in light of prior receipt of radiotherapy for NSCLC, we found that having received radiotherapy before IL-2 led to longer PFS and OS times compared with patients who had not had prior radiotherapy. No such results were found for patients given cisplatin but not IL-2. We further found that patients who had had any prior radiotherapy or prior extracranial radiotherapy had higher TLC, lower neutrophil counts, and lower NLR than those who had no prior radiotherapy which generally are associated with better treatment efficacy and longer survival (16, 17). To our knowledge, this was the largest such analysis undertaken to date, and its results strongly suggest that having had radiotherapy may improve the efficacy of immune therapy other than checkpoint inhibitors. These findings are consistent with the results of several preclinical studies indicating significant, synergistic antitumor effects achieved by combining radiotherapy with immunotherapy. Our findings thus seem to demonstrate that combining radiotherapy with immunotherapy other than the previously studied anti-PD1/PDL1 can indeed induce a “radio-memory” effect.

IL-2, also known as T-cell growth factor, includes a range of bioactive cytokines produced primarily by activated CD4+ T cells and CD8+ T cells, acts as a growth factor for all T-cell subsets and can also promote the activation of B-cell proliferation (18, 19). IL-2 is also important in the regulation of the immune response, including antibody responses, hematopoiesis, and tumor surveillance. Numerous animal models have shown that combining radiotherapy with IL-2 has a synergistic antitumor effect (20–23) and has been shown to be useful clinically in oral cancer (24), renal cell carcinoma (25), and prostate cancer (26). Our results are consistent with these studies. In a study published in 2011, Koji suggested that radiotherapy combined with IL-2 may have radiopharmaceutical effects (27); however, to our knowledge, no studies to date have demonstrated a radio-memory effect.

In our study, patients given intrapleural IL-2 who had previously received radiotherapy for NSCLC had better OS than those who had not had radiotherapy (p = 0.0116, Figure 2C), but no differences were found in short-term efficacy or PFS between these to groups (p = 0.18, Figure 2A). We further found better PFS and OS among patients who had received extracranial irradiation than among those who had not received extracranial irradiation (p = 0.046, Figure 2B; p = 0.0003, Figure 2D). These findings may reflect the following. First, compared to extracranial radiotherapy, cranial radiotherapy will damage more lymphocyte cells and some believe that cranial irradiation cannot change the immune microenvironment in the brain (28). Second, the immune microenvironment within the brain may not change because of the presence of the blood-brain barrier. Even if such changes in the immune system did occur within the brain, it is unlikely that this effect would extend to the immune microenvironment throughout the body, as the blood-brain barrier serves as an obstacle.

Typically the choice of radiation dose, distribution, sequence, and target area is made to ensure thorough destruction of tumor cells while minimizing damage to surrounding normal tissues. When radiotherapy is used as an intervention for immunization, however, this classical approach may require adjustment. For example, it may not be necessary to include the entire tumor area to high-dose radiation, because exposing only a part of the tumor may be required to trigger the immune system. Radiation dose and segmentation schemes that trigger an immune response probably depend on many unknown factors, but the required dose is likely to be much lower than the dose required for definitive radiotherapy, which would in turn reduce the likelihood of adverse reactions. Finally, proton therapy may be more suitable than photon therapy for combining with immune therapy, as proton therapy doses are usually lower and protons may have an as-yet unrecognized role in immunotherapy. However, more comprehensive research in this area is required before recommendations can be made.

Our study of patients with NSCLC who also developed MPE involved a large number of patients with which to analyze the overall clinical effect of previous radiotherapy when those patients were given IL-2. Nevertheless, our study had several limitations, chief among them its retrospective nature, with the attendant unclear inclusion criteria and somewhat inaccurate statistical analyses. Second, the effects on the clinical endpoints studied (OS and PFS) were relatively modest, and the statistical significance levels were marginal. Third, our data could not shed light on the mechanism underlying the radio-memory effect of previous radiotherapy. Also, it is possible that bias may have been introduced by differences in standards of living among patients, perhaps including distance from and access to radiotherapy facilities. Overall, although this study could be considered hypothesis-generating; its conclusions should be validated through prospective controlled trials. From surgery to medicine, and from radiotherapy to immunotherapy, many approaches have been attempted to eradicate cancer. However, single treatments have had relatively modest success at best, and hence the greatest challenge faced by modern-day oncologists is to identify the optimal combinations of existing forms of cancer therapy.

Our findings suggest that previous receipt of radiotherapy for NSCLC may enhance the efficacy of IL-2 for treating MPE and improve outcomes for such patients. They further suggest that the radio-memory effect is not restricted to combining radiotherapy with PD1/PDL1 inhibitors but may extend to other immunotherapy agents. Future clinical trials involving radiotherapy and immunotherapy should consider this observation in designing more rational regimens.

JmY and JbY designed the study. DC, XS, HW, WM, YW, YM, ZG, and SC participated in the collection and analysis the data. DC and XS wrote the manuscript. KL and JbY were responsible of the critical review and revision of this manuscript. All authors provided the approval of the final manuscript for submission.