Table 2  Evaluation of concomitant adenosine-axis blockade in murine models of solid malignancies.
Combinatorial schemes   Treatments   Tumor model   Outcome of concomitant adenosine axis blockade depends on presence/unhindered function of   Impact on the TME
CD73 inhibition & A2AR antagonism  ➣ anti-CD73mAb:
TY/23 (384)
➣ A2AR pharmacologic antagonist:
SCH58261 (384)  ➣ Breast: 4T1.2 (384)
➣ Melanoma:
B16-F10 (384)
LWT1 (384)  ➣ Metastasis formation ↓ (384)
➣ Survival ↑ (384)
NK cells > CD8+ T cells (384)
IFN-γ (384)
Perforin (partial dependence) (384)
PD-1 ICB & CD73 inhibition  ➣ anti-PD-1mAb:
RMP1-14 (382, 385)
➣ anti-CD73mAbs:
Oleclumab (385)
TY/23 (382)  ➣ Breast: 4T1.2 (382)
➣ Colon:
CT26 (385)
MC38 (382)
➣ Prostate: RM-1 (382)  ➣ Primary tumor expansion rate ↓ (382, 385)
➣ Survival ↑ (382, 385)  ↑ Tumor-specific CD8+ T cells (382, 385)↑ IFN-γ mRNA (382)
PD-1 ICB & CD38 inhibition  ➣ anti-PD-L1mAb:
9G2 (96)
➣ anti-CD38mAb:
NIMR-5 (96)
➣ CD38 pharmacologic inhibitor:
Rhein (96)  ➣ Lung:
344SQ (96)
LLC-JSP (96)  ➣ Primary tumor expansion rate ↓ (96)
➣ Metastasis formation ↓ (96)  ↑ CD8+ T cells (96)↑ CD44hiCD62Llo CD8+ T cells (96)↓ PD-1+TIME3+ CD8+ T cells (96)↑ CD4+ICOS+ T cells (96)↓ Tregs (96)↓ MDSCs (96)
PD-1 ICB & A2AR antagonism  ➣ anti-PD-L1:
9G2 (mAb) (96)
B7-DC/Fc (400)
➣ anti-PD-1mAb:
RMP1-14 (396, 401)
➣ A2AR antagonists:
SCH58261 (96, 394, 401)
ZM241385 (400)
SYN115 (401)
CPI-444 (396)  ➣ Breast:
AT3 (401)
4T1.2 (394, 401)
➣ Melanoma: B16-F10 (394)
➣ Colon:
MC38 (396, 401)
CT26 (396)
➣ Lung:
344SQ (96)
LLC-JSP (96)
➣ Lymphoma: EL4 (400)  ➣ Primary tumor expansion rate ↓ (96, 396, 400, 401)
IFN-γ (401)
Retained in perforin KO mice (401)
➣ Metastasis formation ↓ (394, 401)
Tumor CD73 (394)
NK cells > CD8+ T cells (394)
➣ Survival ↑ (394, 396, 401)
CD8+ T cells > NK cells (394)  ↑ IFN-γ+ CD8+ or tumor-specific T cells (401)↑ GzB+ CD8+ T cells (401)↑ NK cells (394)
PD-1 ICB & A2BR antagonism  ➣ anti-PD-1mAb:
RMP1-14 (359)
➣ A2BR antagonist:
PSB1115 (359)  ➣ Melanoma: B16-F10 (359)
➣ Breast: 4T1.2 (359)  ➣ Metastasis formation ↓ (359)
➣ Survival ↑ (359)
CTLA-4 ICB & CD73 inhibition  ➣ anti-CTLA-4mAbs:
9H10 (389)
UC10-4F10 (382)
➣ CD73 pharmacologic inhibitor:
APCP (389)
➣ anti-CD73mAb:
TY/23 (382)  ➣ Breast: 4T1.2 (382)
➣ Melanoma: B16F10 (389)
➣ Colon: MC38 (382)
➣ Prostate: RM-1 (382)  ➣ Primary tumor expansion rate ↓ (382, 389)
CD8+ >> CD4+ T cells (382)
➣ Survival ↑ (382)  ↑ CD8+, CD4+ T cells (389)↑ Tumor-specific CD8+ T cells (382)↑ IFN-γ, T-bet mRNA (382)↑ IFN-γ (389)
CTLA-4 ICB & A2AR antagonism  ➣ anti-CTLA-4mAb:
9H10 (389)
➣ A2AR antagonist:
ZM241365 (389)  ➣ Melanoma: B16F10 (389)  ➣ Primary tumor expansion rate ↓ (389)  ↑ CD8+ T cells (389)↑ IFN-γ, GzB (389)
CTLA-4 ICB & A2BR antagonism  ➣ anti-CTLA-4mAb:
UC10-4F10 (359)
➣ A2BR antagonist:
PSB1115 (359)  ➣ Breast: 4T1.2 (359)
➣ Melanoma: B16-F10 (359)  ➣ Metastasis formation ↓ (359)
➣ Survival ↑ (359)
ACT & CD73 inhibition  ➣ T cells:
2C (SIY-specific) (378)
Reactive to ID8 (378)
OT-I (OVA-specific) (378)
➣ CD73 pharmacologic inhibitor:
APCP (378)
➣ anti-CD73mAb:
TY/23 (378)  ➣ Melanoma: B16-SIY (378)
➣ Ovarian: ID8 (378)
➣ Lymphoma:
EG7 (EL4-OVA) (378)  ➣ Primary tumor expansion rate ↓ (378)
➣ Survival ↑ (378)  ↑ Adoptively transferred T cells (378)
ACT & A2AR antagonism  ➣ T cells:
anti-HER2 CAR+ (135)
OT-I (OVA-specific) (388, 396)
TDLN-derived (402)
Reactive to CMS4 (38)
➣ A2AR antagonists:
CPI-444 (396)
ZM241385 (38, 135, 402)
KW6002 (402)
SCH58261 (135, 388)  ➣ Breast: E0771- HER2 (135)
➣ Melanoma: B16-OVA (396)
➣ Ovarian: ID8-OVA (388)
➣ Fibrosarcoma:
MCA205 (402)
24JK-HER2 (135)
➣ Sarcoma CMS4 (38)  ➣ Primary tumor expansion rate ↓ (135, 396)
PD-1 ICB (135)
IFN-γ (135)
➣ Metastasis formation ↓ (38, 402)
Non-myeloablative pretreatment (402)
➣ Survival ↑ (135, 388, 396, 402) PD-1 ICB (135)  ↑ Adoptively transferred T cells (396)↑ Tbet, 41BB, CD69 in/on adoptively transferred CD8+ cells (396)↑ IFN-γ+ adoptively transferred T cells (135)↑ Stimulation-induced IFN-γ, TNF-α production by adoptively transferred CD8+ T cells (396)↑ Stimulation-induced IFN-γ production by adoptively transferred CD8+ or CD4+ T cells (402)↑ Tbet, 41BB in/on endogenous CD44+ CD8+ cells (396)↑ Stimulation-induced IL-2, IFN-γ, TNF-α production by endogenous CD8+CD44+ T cells (396)
ACT & intratumoral hypoxia aversion  ➣ Respiratory hyperoxia (60%O2)
➣ T cells:
TDLN-derived (293)  ➣ Melanoma: B16-F10 (293)
➣ Fibrosarcoma: MCA205 (293)  ➣ Primary tumor expansion rate ↓ (293)
Host A2AR (293)
➣ Metastasis formation ↓ (293)  ↑ Adoptively transferred T cells (293)↑ IFN-γ+ endogenous/adoptively transferred CD8+ T cells (293)
Radiotherapy & CD73 inhibition  ➣ Radiotherapy:
Single local dose of 20Gy (403, 404)
➣ anti-CD73mAb:
Unspecified (403)
TY/23 (404)  ➣ Breast: TSA (403, 404)  ➣ Primary tumor expansion rate ↓ (403, 404)
BATF3 (403)  ↑ CD103+DCs (403)↑ CD8a+ DCs (404)↑ CD40 on CD8a+ DCs (404)↑ CD8+T cells (404)↑ CD69 on CD8+T cells (404)↑ CD8+T cell/Treg ratio (403)↓ Tregs (404)
Chemotherapy & CD73 inhibition  ➣ Chemotherapy:
Doxorubicin (405)
Paclitaxel (405)
➣ anti-CD73mAb:
TY/23(405)  ➣ Breast:
4T1.2 (405)
AT3 (405)  ➣ Primary tumor expansion rate ↓ (405)
Partially retained in SCID mice lacking T cells, NK cells and functional B cells (405)
CD8+ T cells (405)
➣ Survival↑ (405)  ↑ Tumor-specific CD8+ T cells (405)↑ IFN-γ (405)
Chemotherapy & CD39 inhibition  ➣ Chemotherapy:
Mitoxantrone (406)
Oxaliplatin (406)
➣ CD39 pharmacologic inhibitor:
ARL67156 (406)  ➣ Colon: CT26 (406)
➣ Fibrosarcoma: MCA205 (406)  ➣ Primary tumor expansion rate ↓ (406)
T cells (406)
Knockdown of tumor Atg5 (406)  ↑ Extracellular ATP (406)↑ DCs (406)↑ IFN-γ+ CD4+, CD8+ T cells (406)↑ IL-17A+ γδ T cells (406)↑ IFN-γ (406)
Chemotherapy & A2R antagonism  ➣ Chemotherapy:
Doxorubicin (359, 405, 407)
Dacarbazine (398)
Oxaliplatin (398, 407)
➣ A2R antagonists:
SCH58261(A2AR) (405)
PSB1115 (A2BR) (359, 398)
AB928 (A2AR&A2BR) (407)  ➣ Breast:
4T1.2 (405)
AT3 (359, 405, 407)
➣ Melanoma: B16-F10 (398)  ➣ Primary tumor expansion rate ↓ (398, 405, 407)
Tumor CD73 (405)
➣ Survival ↑ (359)  ↑ CD8+ T cells (398)↑ Tumor-specific CD8+ T cells (407)↑ NKT cells (398)↑ GzB (398)
Targeted therapy & CD73 inhibition  ➣ anti-ErbB2 mAb
7.16.4 (408)
➣ anti-CD73 mAb
TY/23 (408)  ➣ Breast:
H2N100 (408)
TUBO (408)
ErbB2-overexpressing mice (408)  ➣ Primary tumor expansion rate ↓ (408)
Tumor CD73 (408)
B cells, T cells or NK cells (408)
➣ Spontaneous tumor formation ↓ (408)
➣ Metastasis formation ↓ (408)
➣ Survival ↑ (408)  ↑ CD8+ T cells (408)↑ CD4+ FOXP3− T cells (408)↓ MDSCs (408)
Targeted therapy & A2AR antagonism  ➣ BRAF inhibitor:
PLX4720 (393)
➣ MEK inhibitor:
Trametinib (393)
➣ A2AR antagonist:
SCH58261 (393)  ➣ Melanoma:
BRAFV600E-PTEN-deficient mice (393)
BRAFV600E LWT1 (393)  ➣ Primary tumor expansion rate ↓ (393)
➣ Metastasis formation ↓ (393)
TDLN, tumor-draining lymphnode.