Table 4 The potential clinical application of radiotherapy combined with phagocytosis checkpoints-associated immunotherapy.

Biomarkers for sensitivity to radiotherapy

CD47

CD47 has been upregulated in radioresistant breast cancer cells.

[59]

PD-L1

Overexpression of PD-L1 is a helpful biomarker of radiotherapy treatment failure in HPV-negative head and neck squamous cell carcinoma.

[202]

Overexpression of PD-L1 is a main marker to radioresistance in lung adenocarcinoma.

[203]

Low expression of PD-L1 is correlated with radioresistance and poor prognosis in head and neck squamous cell carcinoma.

[204]

High expression of PD-L1/PD-1 is related to tumor cells sensitivity to radiotherapy in head and neck cancers

[205]

CD24

The lack of CD24 at the level of primary clonogenic blasts is related to irradiation resistance in B-lineage acute lymphoblastic leukemia patients.

[206]

The CD24-negative breast cancer stem cells are markers of radioresistance.

[207]

The CD24-positive pancreatic cancer stem cells are resistant to radiotherapy.

[208]

CRT

Glioblastoma cells overexpressing CRT have increased tumor cells sensitivity to radiotherapy.

[209]

Diverse radiotherapy (RT) plans

RT dose fraction

High-dose RT (12 Gy) to primary tumor site primes T cells and low dose RT (1 Gy × 2 fractions) to secondary site promotes M1 macrophage polarization and NK cell infiltration.

[210]

Low-dose RT (2 Gy X 1 fraction) promotes systemic antitumor effects of hypofractionated RT (8 Gy X 3 fractions) combined with anti-PD1 therapy.

[211]

Both a single-fraction dose of 5 Gy and a fractionated schedule (20 Gy /5 fractions) have the same anti-tumor efficiency when RT is combined with CD47 blockade.

[67]

Both low-dose fractionated and hypofractionated RT did not enhance progression-free survival and overall survival compared to anti-PD-L1 inhibition alone in metastatic NSCLC.

[33]

RT types

Proton radiation could upregulate “eat me” signal protein CRT expression on the tumor cells to promote tumor antigen presentation by phagocytes and further increase infiltration of CD8+ T cells.

[212]

The carbon ion therapy in combination with anti-PD-1 antibody not only can upregulate CRT but also increase infiltration of CD4+ and CD8+ T cells compared to conventional radioimmunotherapy.

[213]

Other new radiotherapy styles such as spatially fractionated RT and FLASH RT also have antitumor immune responses and can combine with immunotherapy to produce more effective antitumor efficiency.

[214]

Targeting strategies for phagocytosis checkpoints-associated immunotherapy

Antibody

Anti-CD47 antibody Hu5F9-G4 combined with rituximab (anti-CD20) inhibits B-cell non-Hodgkin’s lymphoma progression by increasing macrophage-mediated phagocytosis in a phase 1b study.

[25]

Anti-CD47 antibody Hu5F9-G4 has a well-tolerated anti-tumor efficiency both in solid tumors and hematologic tumors.

[26]

Anti-SIRPα antibody is a promising antitumor drug with fewer hematologic toxicities side effects because of the confined expression of SIRPα on normal cells compared with CD47.

[49]

Anti-SIRPα antibody promotes phagocytosis of macrophages, activation of DCs and further increases cross-priming tumor-specific CD8+ T cells.

[215]

Small molecule inhibitors

The MYC inhibitor JQ1 downregulates CD47 and PD-L1 expression on the tumor cells to increase antitumor immune response.

[51]

The QPCTL inhibitor regulates CD47 pyroglutamate formation to interfere the binding with SIRPα promoting tumor cell killing by macrophages and neutrophils.

[216]

The EGFR inhibitor gefitinib inhibits the expression of CD47 and increases the expression of CRT, which promotes tumor cell phagocytosis by monocyte-derived dendritic cells in human NSCLC.

[217]

Peptide

A macrocyclic peptide D4-2 can block CD47-SIRPα interaction by selectively binding with g-V-like domain of SIRPα, which further promotes macrophage-mediated phagocytosis.

[218]

The novel peptide pep-20 combined with RT (a single dose of 20 Gy) blocks the CD47/SIRPα interaction by binding to the CD47-IgV domain and inhibiting SIRPα tyrosine phosphorylation of ITIMs, resulting in promoting macrophage-mediated phagocytosis and activating antitumor T-cell immune response.

[38]

A peptide named hEL-RS17 could bind to CD47 on tumor cells and block the signaling of CD47-SIRPα.

[219]

Nanomaterials

A nanobioconjugate engager carrying both anti-HER2 antibodies and CRT to increase the breast cancer cells phagocytosis and tumor antigen presentation by macrophages.

[220]

An engineered biomimetic nanozyme CD47@CCM-Lap-CuS NP, its near-infrared laser irradiation can generate photothermal therapeutic effects on CD47-overexpressing cancer cells.

[221]

The integration of nanoscale metal–organic frameworks enabled radiotherapy with checkpoint blockade immunotherapy to have both local and systemic antitumor effects.

[222]

Additional injection of NBTXR3 nanoparticles can enhance infiltration and activation of cytotoxic immune cells and antitumor effects of the combination of proton therapy and anti-PD-1 on both irradiated and unirradiated tumors.

[223]

A bridging-lipid nanoparticle(B-LNP) with dual targeting to irradiation-triggered CD47 and PD-L1 promotes macrophages to engulf tumor cells, antigen presentation and T cell recruitment in irradiated glioma.

[170]

Multiple immunotherapy regimens

The addition of anti-PD-L1 antibody promotes immune response to the treatment resistance of combination therapy of radiotherapy and anti-CTLA4.

[224]

Combining two types of phagocytosis checkpoint drugs (anti-SIRPα and anti-PD-1) with RT could activate robust adaptive antitumor immune responses in colorectal cancer.

[60]

Sequence of RT and phagocytosis checkpoints-associated immunotherapy

Concurrent therapy

The concurrent administration of anti-PD-L1 and fractionated radiotherapy has a more synergistic antitumor effect compared to sequential administration in colon carcinoma and breast cancer.

[90]

Patients treated with RT combined with anti-PD-1 within four weeks had better antitumor response than more than four weeks in melanoma brain metastases patients.

[225]

Sequential therapy

The administration of RT before ipilimumab has better overall survival and less regional recurrence compared with RT after ipilimumab in melanoma brain metastases.

[226]

Giving RT before immunotherapy has a better overall response rate compared with RT before immunotherapy in 512 patients with cancer metastasis.

[227]

RT before immunotherapy has superior survival compared with the reverse sequence of therapy in patients with melanoma brain metastases.

[228]

Giving anti-PD-1 after irradiation can observe abscopal effects but delivering of anti-PD-1 before irradiation inhibits abscopal activity by promoting infiltration of CD8+ T cells in both primary and secondary tumor in colorectal tumor.

[229]

But, administration of ipilimumab before RT had more effective antitumor efficiency compared with administration of ipilimumab after RT in advanced melanoma patients.

[230]

Patient selection

Molecular gene biomarkers

A kind of gene signature constituted of six tumor-infiltrating B lymphocyte-specific genes can predict prognosis and response of RT and immunotherapy, which low-risk gene signature group is associated with more immune cell infiltration and better prognosis in lung adenocarcinoma.

[231]

A radiosensitivity index (RSI) model including 10 genes is a potential biomarker for radioimmunotherapy which low RSI is associated with higher antigen presentation, higher M1 proportion, richer T cell-inflamed activity and IFN-γ response.

[232]

A PD-L1 tumor proportion score (TPS) ≥ 50% is a biomarker to select patients who can be treated with pembrolizumab and risk-adapted radiotherapy in locally advanced NSCLC.

[233]

Immune cell biomarkers

Infiltration of CD103+ Tregs and accumulation of lipid metabolism can predict resistance to radioimmunotherapy in glioblastomas.

[234]

The contents of blood samples including circulating cell-free DNA (cfDNA), CD8 + PD1+/PDL1+ PBMCs and 27 microRNAs are early promising biomarkers to predict the response of RT and immunotherapy in oligoprogressive patients.

[235]

A special T-cell signature with low CD8+ naive T-cells and high levels of TIM-3 on multiple T-cell populations at baseline is related to good prognosis in metastatic melanoma patients treated with RT and immunotherapy.

[236]

Clinical radiomic model biomarkers

The CD8 radiomics score is related to progression-free survival, out-of-field abscopal response and overall survival, which can assess tumor heterogeneity and select patients who may benefit from radioimmunotherapy without invasive.

[237]

The 18F-FDG-PET is a prognostic imaging biomarker which is associated with OS and PFS for patients with recurrent NSCLC by using its metabolic tumor volume (MTV), total lesion glycolysis (TLG) and lean body mass corrected SUV peak (SUL peak).

[238]

A clinical-radiomic model using XGBoost algorithm can quantitatively predict pathologic complete response of neoadjuvant radioimmunotherapy in esophageal squamous cell carcinoma.

[239]

AI approach-based biomarkers

A neural network model based on AI approach can simulate tumor growth and treatment response of RT and anti-PD-L1 therapy by integrating pulse interval, radiation dose, drug dose, and timing to study a “causal relationship” and further optimize treatment regimens in radioimmunotherapy.

[240]

High infiltration of phagocytes

High infiltration of CD8+ T cells

High expression of phagocytosis checkpoint molecules

Using tissue microarray (TMA) data indicates that over 60% of patients have high levels of CD47 in ovarian, cervix, gastric, NSCLC, melanoma, glioblastoma multiforme, head and neck cell carcinoma, colon, pancreatic and esophageal cancer and over 40% in hepatocellular carcinoma, urothelial and kidney cancer.

[245]

Different tumors highly express PD-L1, such as NSCLC, breast, prostate, colorectal, hepatocellular carcinoma, melanoma, gastric, and brain tumors.

[246]

CD24 is highly expressed on bladder cancer, liver, prostate, ovarian, lung and breast cancer.

[189]

CRT is highly expressed in triple-negative breast cancer.

[247]