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The Pros and Cons of Radiotherapy Affecting Antitumor Immunity
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The Pros and Cons of Radiotherapy Affecting Antitumor Immunity
The introduction of immunotherapy into cancer treatment has fundamentally changed the clinical management of tumors.
However, only a minority of patients ( approximately 10% to 30% ) show long-term responses to immunotherapy monotherapy.
In addition, many cancer types, including pancreatic cancer and glioma, are resistant to immunotherapy. Due to the immunomodulatory effect of radiotherapy, the combination of radiotherapy and immunotherapy has achieved better therapeutic effects in some clinical trials.
However, radiation therapy is a double-edged sword. At certain doses and fractionation, radiation therapy can also weaken the immune system.
Not all clinical trials have shown that the combination of radiation therapy and immunotherapy can improve survival.
Therefore, elucidating the interaction between radiation therapy and the immune system can help optimize the synergistic effect of radiation therapy and immunotherapy.
The Pros and Cons of Radiotherapy Affecting Antitumor Immunity
Radiation therapy can be used alone or in combination with other treatments such as surgery, chemotherapy, and immunotherapy .
On the one hand, radiotherapy enhances the immunogenicity of tumor cells and improves anti-tumor immunity. On the other hand, radiation therapy may enhance local and systemic immunosuppression in patients in some cases.
Radiation therapy induces local and systemic antitumor immunity
Ionizing radiation promotes the release of double-stranded DNA ( dsDNA ) in the nucleus, increases the permeability of the outer mitochondrial membrane, and triggers the exposure of mitochondrial DNA ( mtDNA ) in the cytoplasm.
Both dsDNA and mtDNA are potent mediators of initiation of the cGAS-STING pathway and subsequent transcription of type I interferons.
Type I interferon signaling is critical in activating DCs, thereby promoting T cell activation and tumor control.
Accumulation of dsDNA in tumor-derived exosomes after radiotherapy also promotes DC recruitment and directly induces DC type I IFN responses, which further promotes CD8+ T cell recruitment and provides a third signal for T cell activation .
To evade T cell attack, MHC class I molecules are either absent or underexpressed in many cancer cells.
Radiation therapy upregulates MHC class I molecules on the surface of tumor cells and enhances TAA production, thereby expanding the repertoire of antigens available for presentation.
Furthermore, calreticulin exposure, HMGB1, and ATP secretion on the cell surface enhanced immunogenicity and prompted immune cell infiltration, thereby promoting immune responses in the tumor microenvironment.
Radiation therapy also increased the abundance of tumor-infiltrating immunostimulatory cells and stimulated the release of pro-inflammatory mediators from tumor cells and stromal cells.
The release of chemokines, such as CXCL9, CXCL10, CXCL11, and CXCL16, leads to the infiltration of DCs, macrophages, and T cells.
In conclusion, by altering the tumor cell phenotype, triggering the hallmark release of immunostimulatory DAMPs, and increasing the number of pro-inflammatory immune cells, radiotherapy sensitizes tumor cells to T cell-mediated antitumor effects and promotes the response to Identification and removal of cancer cells.
Radiation therapy induces immunosuppression and lymphopenia
Radiation therapy leads to the accumulation of dsDNA in cancer cells, which activates cGAS/STING signaling and promotes the transcription of type I IFN genes.
However, interferon signaling can also have deleterious effects, leading to treatment resistance.
Repeated irradiation of tumor cells induces chronic type I interferons and interferon-stimulated gene expression that mediate radiation resistance and metastatic spread through multiple inhibitory pathways.
Both IFN-γ and type I IFN are responsible for upregulating the expression of PD-L1 on tumor cells, which further induces T cell exhaustion and resists antitumor immunity.
IDO is also upregulated by type I IFN and IFN-γ, acting as an immunosuppressive factor. Furthermore, activated STING signaling enhanced the mobilization of Tregs, MDSCs, and eliminated tumor immunogenicity.
Local radiotherapy upregulates the secretion of CCL2 and CCL5, which is associated with the recruitment of Tregs and monocytes.
Recruited monocytes activate Tregs in a TNF-α-dependent manner, reducing the efficacy of radiotherapy.
Furthermore, Tregs enhance the immunosuppressive effect of MDSCs and inhibit the function of effector T cells by secreting IL-10 and TGF-β.
Lymphopenia is one of the most common side effects of radiation therapy. Because the bone marrow is extremely sensitive to radiation, severe bone marrow damage can occur during radiation therapy.
Even relatively low radiation doses can cause temporary functional ablation of the bone marrow. When the bone marrow receives moderate doses of radiation, it takes several years to regain active hematopoiesis.
Higher radiation doses can cause irreversible damage.
Circulating PBMCs are also highly sensitive to ionizing radiation. Repeated daily routine fractionated radiation therapy is cytotoxic enough to deplete migrating immune effector cells.
Another mechanism by which radiation therapy induces lymphopenia is through irradiation of lymphoid organs.
Naive T cells are extremely sensitive to radiation, and even low-dose irradiation of lymphoid tissues can lead to rapid apoptosis mediated by p53.
Furthermore, radiation-induced Gal-1 secretion by tumor cells exhibited T cell pro-apoptotic activity and was associated with lymphopenia and poor survival outcomes.
Combination therapy of radiotherapy and immunotherapy
Over the past decade, several immunotherapeutic drugs have been approved for clinical use in cancer.
Many of these immunotherapeutic drugs have been tested in combination with radioimmunotherapy in the clinic.
Synergy between radiotherapy and immunotherapy
Since radiation therapy has significant immunostimulatory effects, it provides a theoretical basis for combining immunotherapy with different forms of radiation therapy.
Preclinical studies in HNSCC have shown that radiotherapy sensitizes unresponsive HNSCC tumors to PD-L1 inhibition by transforming the tumor microenvironment into an inflammatory environment.
Radiotherapy and anti-PD-L1 antibodies synergistically reduce the accumulation of tumor-infiltrating MDSCs, release T cells from the suppressive tumor immune microenvironment, and enhance antitumor effects.
Radioimmunotherapy can also induce strong antitumor responses mediated by CD8+ T cells outside the irradiated area.
Through the combination of immunotherapy and radiotherapy, patients can achieve local control and regression of metastatic tumors.
Furthermore, the combination of radiotherapy and anti-PD-L1 drugs induced an immune memory effect when fully responding mice were challenged with reimplanted tumor cells.
Since recurrence and distant metastasis are the main causes of cancer-related death, generating memory immune responses can effectively prevent tumor recurrence and metastasis, thereby prolonging the survival time of patients.
Clinical studies have shown encouraging benefits of radioimmunotherapy on patient survival.
The median PFS ( 4.4 months vs 2.1 months, p=0.019 ) and median OS ( 10.7 months vs 5.3 months, p=0.026 ) of patients with advanced non-small cell lung cancer who received Nivolumab after radiotherapy were significantly higher than those who did not receive Patients treated with radiation were significantly longer.
In conclusion, radioimmunotherapy reshaped the suppressive tumor immune microenvironment, promoted the generation of T cell responses, and recognized and eliminated cancer cells from irradiated tumor sites and distant metastases.
In some cases, radiation therapy does not enhance the combined effects of immunotherapy
Immunotherapy eliminates cancer cells by stimulating anti-tumor immune responses that primarily rely on activated CD8+ T cells or utilized immune cells.
Radiation therapy may effectively reduce the efficacy of immunotherapy by upregulating the infiltration of suppressive immune cells and directly damaging circulating lymphocytes, including CD8+ T cells.
Therefore, radiotherapy and immunotherapy do not always show synergistic effects.
Although anti-PD-1 antibody combined with 8Gy×2 irradiation enhanced primary and metastatic tumor control and reversed adaptive immune resistance in a CD8+ T cell-dependent manner, anti-PD after 2Gy×10 irradiation -1 antibody suppressed IFN expression in tumor-specific CD8+ T cells within the DLN, resulting in a lack of efficacy.
This may be due to lymphopenia and immunosuppression induced by low-dose fractionated daily radiation therapy.
Selective nodal radiotherapy is often used in the treatment of localized tumors to address underlying subclinical nodal micrometastases.
However, when combined with anti-CTLA-4 antibodies, selective lymph node irradiation contributed to an immunosuppressive tumor microenvironment, and survival was not prolonged compared with anti-CTLA-4 antibody monotherapy.
Furthermore, although radiotherapy combined with anti-CTLA-4 resulted in tumor regression, PD-L1 expression was concomitantly upregulated, leading to T cell exhaustion and drug resistance.
Consistent with preclinical studies, several clinical trials have shown no combined effect between radiation therapy and immunotherapy.
A phase 3 trial involving prostate cancer showed no significant difference in OS between 8 Gy of RT plus ipilimumab compared with RT alone in patients who had progressed after docetaxel.
Preclinical evidence suggests that the combination of hypofractionated ionizing radiation and ICIs significantly enhances tumor control.
However, clinical trials aimed at evaluating the synergistic effect of nivolumab and SBRT ( 9Gy×3 ) in HNSCC failed to improve ORR.
In addition, as the first FDA-approved autologous cellular immunotherapy, sipuleucel-T improved median survival by 4.1 months compared with placebo.
However, median PFS in the sipuleucel-T group was comparable to that in the sipuleucel-T alone group in patients with metastatic castration-resistant prostate cancer treated with 300 cGy × 10 RT.
In addition, the accumulated antigen-presenting cells and IFN-γ+ T cells were even higher in the Sipuleucel-T alone group.
In conclusion, radiation therapy may weaken the efficacy of immunotherapy in some cases.
Whether immunotherapy and radiotherapy work synergistically is related to many factors.
When radiotherapy is combined with immunotherapy, the immunomodulatory effect of radiotherapy should be fully considered.
Additional investigations are needed to determine optimal radiotherapy regimens, target checkpoints, and patient cohorts to fully assess the efficacy of radioimmunotherapy.
Strategies to enhance the synergistic effect of radiotherapy and immunotherapy
In order to optimize the antitumor effect of radioimmunotherapy, several aspects should be considered, including exploring appropriate radiotherapy regimens, considering the timetable when immunotherapy is combined with radiotherapy, reducing the immunosuppressive effect of radiotherapy, and the availability of some new technologies in radiotherapy. application.
Choosing the Right Radiation Therapy Plan
To optimize the effect of radioimmunotherapy, radiotherapy regimens should be designed to include two factors: dose and fractionation.
Clinicians apply conventional radiation therapy empirically to achieve local tumor control and tolerate toxicity. However, even tolerable lymphopenia can attenuate the efficacy of radiation therapy combined with immunotherapy.
Conventional radiation therapy was developed without consideration of the potential therapeutic effects of the immune system, which often adversely affects the immune system to the detriment of immunotherapy.
The combination of hypofractionated radiation and ICIs can enhance anti-tumor immunity, resulting in significant tumor control. In addition, compared with single high-dose radiotherapy, hypofractionated radiotherapy also has superior curative effect.
Studies report improved efficacy of hypofractionated radiotherapy combined with immunotherapy. For example, anti-PD-1 antibody combined with 8Gy×2 instead of 2Gy×10 enhanced the control of primary and metastatic tumors.
The curative effect of a single dose of 20Gy local radiotherapy is comparable to that of 8Gy×3 and 6Gy×5.
However, fractionated radiotherapy alone significantly improved tumor growth at both primary and secondary tumor sites when combined with anti-CTLA-4 antibodies.
There is a specific therapeutic window when radiotherapy regimens are combined with ICIs.
The ultimate effect of radioimmunotherapy depends on the combined effect of complex effects on the immune system.
It is more appropriate to combine hypofractionated radiotherapy with immunotherapy.
However, clinical trials of radiotherapy combined with immunotherapy are usually based on classical protocols, and the optimal radiotherapy regimen for combined immunotherapy remains to be explored.
Exploring the Timeline for Combining Immunotherapy and Radiation Therapy
Immunotherapy dosing regimens have been reported to have a significant impact on tumor suppression with radiation therapy.
Concomitant administration of radiotherapy and anti-PD‑L1 therapy, rather than sequential therapy, was associated with long-term tumor control.
However, the phase 1 clinical trial of KEYNOTE-001 showed that patients who received any form of radiotherapy before pembrolizumab showed prolonged PFS.
Furthermore, in patients with metastatic HNSCC, nivolumab concomitantly receiving SBRT did not improve ORR compared with nivolumab monotherapy.
Therefore, the optimal sequence may be related to various factors, such as the type of immunotherapy, radiotherapy regimen, tumor characteristics and individual differences.
All these factors should be taken into consideration for better prognosis.
Narrowing down the scope of radiation therapy
The complete cancer immune cycle is critical in immunotherapy, and it is important for radioimmunotherapy to protect lymphocytes during radiotherapy.
In order to reduce the negative impact of radiotherapy on immune cells, irradiation of lymph nodes, bone marrow and blood must be avoided.
Over the past two decades, IMRT and other techniques have made it possible to apply conformal doses to radiation therapy, thereby reducing radiation doses to nonmalignant tissues while ensuring tumoricidal doses to local tumors.
For conventional radiotherapy regimens for various indications, such as NSCLC, cervical cancer, and HNSCC, a full dose of 50-70Gy is usually formulated for the tumor site, and a dose of 45-50Gy is formulated for the DLN to achieve the purpose of preventive coverage.
Since DLN is the main platform for cross-priming of T cells, and T cells in lymphoid tissues are extremely sensitive to radiotherapy, irradiation of tumor-free lymph nodes may interfere with the initiation of anti-tumor immune responses.
Therefore, prophylactic nodal irradiation is not required for patients with negative cervical lymph nodes. Should attach great importance to the protection of lymph nodes.
In addition, T cells in the blood circulation and bone marrow are extremely sensitive to radiation. During radiation therapy, it is necessary to reduce the exposure of blood vessels and bone marrow.
Application of New Technology in Radiation Therapy
The development of new technologies is also an excellent option to minimize the side effects of radiation therapy on the immune system.
Proton radiation therapy was able to reduce the dose delivered to nonmalignant tissues and induce upregulation of histocompatibility antigens and TAAs.
In addition, proton radiotherapy increases the exposure of calreticulin on the surface of tumor cells, thereby increasing the killing effect of CTL on tumor cells. Combining immunotherapy with proton radiation therapy is promising.
Heavy ion radiation therapy ( HIRT ) is becoming a cutting-edge technology for the treatment of malignant tumors. HIRT can vary the energy and superimpose multiple Bragg peaks, allowing for more precise treatment.
Carbon ion radiotherapy was associated with higher OS compared with proton radiotherapy and photon-based IMRT.
During treatment, HIRT will significantly reduce lymphocyte damage. Thus, HIRT enhances the role of the immune system in radioimmunotherapy.
Compared with the conventional dose rate of about 5Gy/min in clinical practice, FLASH radiotherapy can provide dose at an ultra-high dose rate ( >40Gy/s ).
Thus, it reduces normal tissue toxicity while maintaining local tumor control. By delivering a higher dose rate, FLASH radiotherapy reduces treatment time.
The short exposure time significantly reduced irradiation of circulating immune cells.
The efficacy of immunotherapy is highly dependent on the immune system. Immunomodulatory effects should be fully considered in the combination of immunotherapy and other therapeutic methods.
Radiation therapy is an ideal companion due to its stimulating effect on the immune system.
However, radiotherapy has profound immunomodulatory effects, and not all radiotherapy regimens work synergistically with immunotherapy.
Understanding the underlying immune mechanisms of radiotherapy is crucial to improve the synergistic effect of radiotherapy and immunotherapy.
Existing evidence demonstrates that concomitant administration of hypofractionated radiotherapy and immunotherapy is more likely to improve treatment outcomes.
Reducing exposure has also shown the potential to improve patient outcomes.
In addition, technological breakthroughs in radiotherapy techniques offer significant opportunities to create maximum efficacy in radioimmunotherapy.
1. Radiotherapy: Brightness and darkness in the era of immunotherapy. Transl Oncol.2022 May;19:101366.
The Pros and Cons of Radiotherapy Affecting Antitumor Immunity
(source:internet, reference only)