Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Ascierto, Paolo A.; Buonaguro, Luigi; Emens, Leisha A.; Ferris, Robert L.; Fox, Bernard A.; Delgoffe, Greg M.; Galon, Jérôme; Gridelli, Cesare; Merlano, Marco; Nathan, Paul; Odunsi, Kunle; Okada, Hideho; Paulos, Chrystal M.; Pignata, Sandro; Schalper, Kurt A.; Spranger, Stefani; Zarour, Hassane M.; Butterfield, Lisa H.; Puzanov, Igor

doi:10.1186/s40425-019-0798-3

Cited by 16 publications

(8 citation statements)

References 78 publications

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“…The 5-year survival rate of patients with early-stage NSCLC after surgical treatment is 70%-90%; however, approximately 75% of patients lost their opportunity for surgery by the time of initial diagnosis (Goldstraw et al, 2016). Despite important advances in targeted molecular therapies and immunotherapy for lung cancer, drug resistance still limits success (Ascierto et al, 2019), and new biomarkers are warranted for different populations. This will have important implications for improving patients' early diagnosis rates and for discovering novel targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Analysis of prognostic genes in the tumor microenvironment of lung adenocarcinoma

Zhao

Chen

et al. 2020

PeerJ

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Background Prognostic genes in the tumor microenvironment play an important role in immune biological processes and the response of cancer to immunotherapy. Thus, we aimed to assess new biomarkers that are associated with immune/stromal cells in lung adenocarcinomas (LUAD) using the ESTIMATE algorithm, which also significantly affects the prognosis of cancer. Methods The RNA sequencing (RNA-Seq) and clinical data of LUAD were downloaded from the the Cancer Genome Atlas (TCGA ). The immune and stromal scores were calculated for each sample using the ESTIMATE algorithm. The LUAD gene chip expression profile data and the clinical data (GSE37745, GSE11969, and GSE50081) were downloaded from the Gene Expression Omnibus (GEO) for subsequent validation analysis. Differentially expressed genes were calculated between high and low score groups. Univariate Cox regression analysis was performed on differentially expressed genes (DEGs) between the two groups to obtain initial prognosis genes. These were verified by three independent LUAD cohorts from the GEO database. Multivariate Cox regression was used to identify overall survival-related DEGs. UALCAN and the Human Protein Atlas were used to analyze the mRNA /protein expression levels of the target genes. Immune cell infiltration was evaluated using the Tumor Immune Estimation Resource (TIMER) and CIBERSORT methods, and stromal cell infiltration was assessed using xCell. Results In this study, immune scores and stromal scores are significantly associated with the clinical characteristics of LUAD, including T stage, M stage, pathological stage, and overall survival time. 530 DEGs (18 upregulated and 512 downregulated) were found to coexist in the difference analysis with the immune scores and stromal scores subgroup. Univariate Cox regression analysis showed that 286 of the 530 DEGs were survival-related genes (p < 0.05). Of the 286 genes initially identified, nine prognosis-related genes (CSF2RB, ITK, FLT3, CD79A, CCR4, CCR6, DOK2, AMPD1, and IGJ) were validated from three separate LUAD cohorts. In addition, functional analysis of DEGs also showed that various immunoregulatory molecular pathways, including regulation of immune response and the chemokine signaling pathways, were involved. Five genes (CCR6, ITK, CCR4, DOK2, and AMPD1) were identified as independent prognostic indicators of LUAD in specific data sets. The relationship between the expression levels of these genes and immune genes was assessed. We found that CCR6 mRNA and protein expression levels of LUAD were greater than in normal tissues. We evaluated the infiltration of immune cells and stromal cells in groups with high and low levels of expression of CCR6 in the TCGA LUAD cohort. In summary, we found a series of prognosis-related genes that were associated with the LUAD tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Analysis of prognostic genes in the tumor microenvironment of lung adenocarcinoma

Zhao

Chen

et al. 2020

PeerJ

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“…However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. Recent advances in immunotherapy of cancer by means of antibody therapies [ 1 , 2 ] and immune checkpoint blockade [ 3 – 6 ] have prolonged survival of cancer patients, but many patients do not respond to these therapies [ 5 , 7 , 8 ] and those who respond would remain at risk of tumor recurrence [ 6 , 9 , 10 ]. Therefore, a relapse-free cancer cure remains a major challenge for cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets

et al. 2020

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Background Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. Methods We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. Results We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67− and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. Conclusion Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

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“…Mortality remains high in patients with metastatic recurrence of cancers. Recent advances in immunotherapy of cancer by means of antibody therapies ( 45 , 46 ) and immune checkpoint blockade ( 47 – 50 ) have prolonged survival of patients, but many patients do not respond to these therapies ( 49 , 51 , 52 ), and those who respond would remain at risk of tumor recurrence ( 50 , 53 , 54 ). This is because proliferating tumor cells could escape from cancer therapies by i) changing themselves through tumor antigen loss, MHC class I downregulation, mutations in antigen presentation machinery, and upregulation of the immune checkpoint molecules such as PD-L1, as well as by ii) changing their microenvironment through the secretion of immune suppressive cytokines/chemokines that induce Tregs and/or MDSCs for the suppression of anti-tumor immune responses.…”

Section: Immunotherapeutic Targeting Of Tumor Dormancy For the Prevenmentioning

confidence: 99%

The premise of personalized immunotherapy for cancer dormancy

Manjili¹

2020

Oncogene

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Progress in cancer therapies has resulted in improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. To this end, tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients and cancer survivors. Current clinical practice guidelines recommend a “wait and watch” approach for tumor recurrence. This is because of our limited understanding of tumor dormancy. Dormant tumor cells are quiescent, and thus, do not respond to chemotherapies or radiation therapies, and they are not operable. Therefore, immunotherapy is the only option for the treatment of tumor dormancy. However, gaps in our knowledge as to dormancy-specific antigens prevent a relapse preventing vaccine design. Here, we provide a critical review of cancer immunotherapy, and discuss empirical evidence related to naturally-occurring tumor dormancy and treatment-induced tumor dormancy at the site of primary tumor and in distant organs before and after cancer therapies. Finally, we suggest that personalized vaccines targeting dormancy-associated neoantigens, which can be given to patients with early stage disease after the completion of neoadjuvant therapies and tumor resection as well as to cancer survivors could eliminate relapse causing dormant cells and offer a cure for cancer.

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Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Cited by 16 publications

References 78 publications

Analysis of prognostic genes in the tumor microenvironment of lung adenocarcinoma

Analysis of prognostic genes in the tumor microenvironment of lung adenocarcinoma

Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets

The premise of personalized immunotherapy for cancer dormancy

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