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. 2023 Jul 18;42:171. doi: 10.1186/s13046-023-02724-y

Table 3.

Synergistic effect via combination of immunotherapy and HIF inhibitor

Target Immunotherapy agent HIF inhibitor agent Mechanism of HIF inhibitor Cell Cell line Reference
PD-1 PD-1 Ab (clone RMP1–14, rat IgG2a)

PMN-MDSC inhibitor: POG

graphic file with name 13046_2023_2724_Figav_HTML.gif

 Inhibits HIF-1α expression Melanoma Mouse: B16F10

PubChem

CID: 14034912

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/14034912

[105]
Breast cancer

Mouse:

4T1
PD-1 Ab

IDF-11774

graphic file with name 13046_2023_2724_Figaw_HTML.gif

 Inhibits HIF-1α expression Prostate cancer

Mouse:

RM-1

Pubchem CID: 71542096

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/71542096

[106]
PD-L1 PD‐L1 Ab (SP142)

HIF-2α antagonist:

PT2385

graphic file with name 13046_2023_2724_Figax_HTML.gif

PT2399

graphic file with name 13046_2023_2724_Figay_HTML.gif

 Both interfere the heterodimerization of HIF-2α with HIF-β ccRCC Mouse: XP164, XP373, XP453, XP454

PubChem

CID: 91754484

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/91754484

PubChem

CID: 91663289

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/91663289

[107-109]
CTLA-4

CTLA4 mAb

(UC10-4F10; hamster IgG)

anti-RANKL mAb:

denosumab

 Downregulates HIF-1α protein expression Melanoma

Mouse:

B16F10, LWT1

[109]

[110]
Colon carcinoma

Mouse:

CT26

Prostate

carcinoma

 Mouse:RM-1
Prostate adenocarcinoma

Mouse:

Tramp-C1
Fibrosarcoma

Mouse:

MCA1956
PD-1, CTLA-4

PD-1

(clone RMP1-14)

CTLA-4 mAb (clone 9D9)

ENTPD2 inhibitor:

ARL67156

graphic file with name 13046_2023_2724_Figaz_HTML.gif

POM-1

graphic file with name 13046_2023_2724_Figba_HTML.gif

 Inhibit downstream product MDSC to upregulate HIF-1α HCC

Human:

MHCC97L PLC/PRF/5, Hep3B Mouse:

Hepa1-6

PubChem

CID:

146157453

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/146157453

PubChem

CID:

71311259

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/71311259

[111]
PD-1, CTLA4

CTLA-4 Ab (9H10)

PD-1 Ab (clone: 29 F.1A12, 135204)

Ganetespib

graphic file with name 13046_2023_2724_Figbb_HTML.gif

 Inhibits Hsp90 and leads to HIF-1α degradation Colon carcinoma

Mouse:

MC38/gp

100

PubChem

CID:

135564985

URL:

https://pubchem.ncbi.nlm.nih.gov/compound/135564985

[112, 113]

[114]
Melanoma

Human:

melanoma 2338, 2400, 2549, 2559, 2812
PD-L1, PD-1, CTLA-4 Anti-PD-1 (clone RMP1-14) CXCR4 antagonist: X4-136 Inhibits CXCR-4 to positively feedback HIF-1α Melanoma

Mouse:

B16-OVA

[115]

[116]
Anti-PD-L1 (clone: 10F.9G2) Renal Cancer

Mouse:

Renal Cancer Renca DM (Renca-2159-84H)
Anti-CTLA-4 Ab (clone: 9D9)
IL-1 miR-144-3p mimic

COX2 inhibitor: celecoxib

graphic file with name 13046_2023_2724_Figbc_HTML.gif

 Inhibits IL-1β/NF-κB/COX-2/ HIF-1α pathways NSCLC

Human:

A549

PubChem

CID:

349,978,031

URL:

https://pubchem.ncbi.nlm.nih.gov/substance/349978031

[117]

Abbreviation: ccRCC Clear cell renal cell carcinoma, HCC Hepatocellular carcinoma (HCC), MDSC Myeloid derived suppressor cells, NSCLC Non-small cell lung cancer, PD-1 Programmed cell death protein 1, PD-L1 Programmed death-ligand 1, CTLA4 Cytotoxic T-lymphocyte-associated protein 4, CXCR4 CXC-chemokine receptor 4, COX2 Cyclooxygenase-2