Compositions and methods comprising digital signatures to predict response and resistance to targeted therapy and immunotherapy

1. A method of determining whether inhibition of programmed cell death protein 1 (PD1) in a subject with neoplasia will result in clinical benefit in the subject comprising:

obtaining a test sample from a subject having or at risk of developing neoplasia;

determining the expression level of tumor immune dysfunction and exclusion (TIDE)-associated genes in the test sample, wherein the TIDE-associated genes comprise serine proteinase inhibitor (serpin) Family B Member 9 (SerpinB9), transforming growth factor beta-1 (TGFβ-1), prolyl endopeptidase (FAP), vascular endothelial growth factor A (VEGFA), angiopoietin 2 (ANGPT2), cluster of differentiation 274 (CD274), interferon gamma (IFNγ), and alpha-mannosidase 2 (MAN2A1);

comparing the expression level of the TIDE-associated genes in the test sample with the expression level of the corresponding genes in a reference sample;

determining that inhibition of PD1 in the subject with neoplasia will result in clinical benefit in the subject when

i. the expression level of SerpinB9, TGFβ-1, FAP, VEGFA, ANGPT2, and MAN2A1 in the test sample is lower than the level of the corresponding gene in the reference sample, and

ii. the expression level of CD274 and IFNγ in the test sample is higher than the level of the corresponding gene in the reference sample; and

administering to the subject an effective amount of a PD1 inhibitor, wherein the PD1 inhibitor comprises a PD1 antibody, thereby treating the neoplasia.

2. The method of claim 1 , wherein clinical benefit in the subject comprises complete or partial response as defined by response evaluation criteria in solid tumors (RECIST), stable disease as defined by RECIST, or long-term survival in spite of disease progression or response as defined by immune-related response criteria (irRC).

3. The method of claim 1 , wherein the test sample is obtained from the neoplasia tissue or from tumor microenvironment or from tumor-infiltrating immune cells.

4. The method of claim 1 , wherein the sample comprises a biological sample, wherein the biological sample comprises a plasma sample or a blood sample.

5. The method of claim 1 , wherein the sample comprises deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).

6. The method of claim 5 , wherein the sample comprises ribonucleic acid (RNA).

7. The method of claim 1 , wherein the reference sample is obtained from healthy normal tissue, a neoplasia that received a clinical benefit from PD1 inhibition, or neoplasia that did not receive a clinical benefit from PD1 inhibition.

8. The method of claim 1 , wherein the expression level of the TIDE-associated genes is detected via an Affymetrix Gene Array hybridization, next generation sequencing, ribonucleic acid sequencing (RNA-seq), a real time reverse transcriptase polymerase chain reaction (real time RT-PCR) assay, immunohistochemistry (IHC), immunofluorescence.

9. The method of claim 1 , wherein the expression level of the TIDE-associated genes is detected via RNA-seq and the reference sample is obtained from healthy normal tissue from the same individual as the test sample or one or more healthy normal tissues from different individuals.

10. The method of claim 1 , wherein the expression level of the TIDE-associated genes is detected via RT-PCR and wherein the reference sample is obtained from the same tissue as the test sample.

11. The method of claim 1 , wherein the subject is a human.

12. The method of claim 1 , wherein the subject has not yet received treatment with a CTLA4 inhibitor, a PD1 inhibitor, or a PD-L1 inhibitor.

13. The method of claim 1 , wherein the PD1 inhibitor comprises pembrolizumab or nivolumab.

14. The method of claim 1 , further comprising treating the subject with a chemotherapeutic agent, radiation therapy, cryotherapy, hormone therapy, or immunotherapy.

15. The method of claim 14 , wherein the chemotherapeutic agent comprises dacarbazine, temozolomide, nab-paclitaxel, paclitaxel, cisplatin, or carboplatin.

16. The method of claim 1 , further comprising administering an inhibitor of a TIDE-associated gene with a higher level of expression compared to the level of the TIDE-associated gene in the reference sample, wherein the TIDE-associated gene comprises CD274 or IFNγ.

17. The method of claim 1 , wherein the neoplasia comprises melanoma, kidney cancer, urothelial carcinoma, lung cancer, bladder cancer, leukemia, endometrial cancer, neuroblastoma, or breast cancer.

18. The method of claim 1 , wherein the neoplasia comprises kidney renal clear cell carcinoma, head neck squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, breast invasive carcinoma, kidney renal papillary cell carcinoma, cholangiocarcinoma, uterine corpus endometrial carcinoma, stomach adenocarcinoma, kidney chromophobe, bladder urothelial carcinoma, prostate adenocarcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, thyroid carcinoma, or lung squamous cell carcinoma.