Recent studies highlighted the clinicopathologic importance of tumor microenvironment (TME) in delineating molecular attributes and therapeutic potentials. However, the overall TME cell-infiltration landscape in non-squamous NSCLC have not been comprehensively recognized. In this study, we employed consensus non-negative matrix factorization (NMF) molecular subtyping to determine the TME cell infiltration patterns and identified three TME clusters (TME-C1, -C2, -C3) characterized by distinct clinicopathologic features, infiltrating cells, and biological processes. Proteomics analyses revealed that cGAS-STING immune signaling mediated protein and phosphorylation level were significantly upregulated in inflamed-related TME-C2 clusters. The TMEsig-score extracted from the TME-related signature divided NSCLC patients into high- and low-score subgroups, where a high score was associated with favorable prognosis and immune infiltration. Genomic landscape revealed that patients with low TMEsig-score harbored greater somatic copy number alternations and higher mutation frequency of driver genes involving STK11, KEAP1 and SMARCA4 et al. Drug sensitivity analyses suggested that tumors with high TMEsig-score were responsible for favorable clinical response to immune check-point inhibitors (ICI) treatment. In summary, this study highlights that comprehensive recognizing of the TME cell infiltration landscape will contribute to enhance our understanding of TME immune regulation and promote effectiveness of precision biotherapy strategies.
Hao Chen, Tongchao Zhang, Yuan Zhang, Hao Wu, Zhen Fang, Yang Liu, Yang Chen, Zhe Wang, Shengtao Jia, Xingzhao Ji, Liang Shang, Fengying Du, Jin Liu, Ming Lu, Wei Chong
Understanding the immune response to dengue virus (DENV) is essential for developing a dengue vaccine that is protective against all four DENV serotypes. We evaluated the immune response post-vaccination (live attenuated tetravalent dengue vaccine TV005 or trivalent admixture) and post-challenge with DEN2Δ30 (Tonga/74) to better understand the importance of homotypic immunity in vaccine protection. Significant increases in IP-10 expression were observed following receipt of either the trivalent or tetravalent vaccine. After challenge, a large increase in IP-10 expression was observed in the placebo (FCH = 4.5) and trivalent admixture groups (FCH = 2.3) but not in the tetravalent vaccine group (FCH = 1.1). MCP-1, IL-1RA, and MIP-1β exhibit a similar pattern as IP-10. These results demonstrate protective effects of trivalent and tetravalent vaccines against DENV, but suggest a better protective effect with the tetravalent vaccine compared to the trivalent admixture. We also explored the post-vaccination and post-challenge immune response differences between black participants and white participants. White participants respond to vaccine differently from black participants, with black participants receiving trivalent and tetravalent vaccines respond strongly and white participants only transiently in trivalent group. In response to challenge, white participants elicit a stronger response than black participants. These results may explain why white participants may have a more vigorous DENV immune response than black participants reported in literature.
Ruixue Hou, Lewis E. Tomalin, Jessica Pintado Silva, Seunghee Kim-Schulze, Stephen S. Whitehead, Ana Fernandez-Sesma, Anna P. Durbin, Mayte Suárez-Fariñas
Chronic lymphocytic leukemia (CLL) results from expansion of a CD5+ B-cell clone that requires interactions with other cell types, including T cells. Moreover, CLL patients have elevated circulating IL17A+ and IL17F+ CD4+ T cells (Th17s), with higher IL17A+Th17s correlating with better outcomes. We report that CLL Th17s express more miR155, a Th17 differentiation regulator, than control Th17s, despite naïve CD4+ T cell (TN) basal miR155 levels being similar in both. We also found that CLL cells directly regulate miR155 levels in TN, thereby affecting Th17 differentiation by documenting that: co-culturing TN with resting (Brest) or activated (Bact) CLL cells alters the magnitude and direction of T-cell miR155 levels; CLL Bact promote IL17A+ and IL17F+ T cell generation by a miR155-dependent mechanism, confirmed by miR155 inhibition; co-cultures of TN with CLL Bact lead to a linear correlation between the degree and direction of T-cell miR155 expression changes and IL17F production, but not IL17A; Bact-mediated changes in TN miR155 expression correlate with outcome, irrespective of IGHV mutation status, a strong prognostic indicator. Together, the results identify a previously unrecognized CLL Bact-dependent mechanism, upregulation of TN miR155 expression and subsequent enhancement of IL17F+ Th17 generation, that favors better clinical courses.
Byeongho Jung, Gerardo Ferrer, Pui Yan Chiu, Rukhsana Aslam, Anita Ng, Florencia Palacios, Michael Wysota, Martina Cardillo, Jonathan E. Kolitz, Steven L. Allen, Jacqueline C. Barrientos, Kanti R. Rai, Nicholas Chiorazzi, Barbara Sherry
In many solid cancers, tumor-associated macrophages (TAM) represent the predominant myeloid cell population. Antigen (Ag) cross-presentation leading to tumor Ag-directed cytotoxic CD8+ T cell responses is crucial for anti-tumor immunity. However, the role of recruited monocyte-derived macrophages, including TAM, as potential cross-presenting cells is not well understood. Here, we show that primary human as well as mouse CD206+ macrophages are effective in functional cross-presentation of soluble self and non-self Ag, including tumor-associated Ag (TAA) as well as viral Ag. To confirm the presence of cross-presenting TAM in vivo, we performed phenotypic and functional analysis of TAM from B16-F10 and CT26 syngeneic tumor models and have identified CD11b+F4/80hiCD206+ TAM to effectively cross-present TAA. We show that CD11b+CD206+ TAM represent the dominant tumor-infiltrating myeloid cell population, expressing a unique cell surface repertoire, promoting Ag cross-presentation and Ag-specific CD8+ T cell activation comparable to cross-presenting CLEC9A+ dendritic cells (cDC1). The presence of cross-presenting CD206+ TAM is associated with reduced tumor burden in mouse syngeneic tumor models and with improved overall survival in cutaneous melanoma patients. Therefore, the demonstration of effective Ag cross-presentation capabilities of CD206+ TAM, including their clinical relevance, expands our understanding of TAM phenotypic diversity and functional versatility.
Madhura Modak, Ann-Kathrin Mattes, Daniela Reiss, Wioletta Skronska-Wasek, Rebecca Langlois, Nicolas Sabarth, Renate Konopitzky, Fidel Ramírez, Katharina Lehr, Tobias Mayr, David Kind, Coralie Viollet, Lee Kim Swee, Jutta Petschenka, Karim Christian El Kasmi, Elfriede Noessner, Kerstin Kitt, Stefan Pflanz
Insight into processes that determine CD8+ T cell memory formation has been obtained from infection models. These models are biased toward an inflammatory milieu and often employ high avidity CD8+ T cells in adoptive transfer procedures. It is unclear whether these conditions mimic the differentiation processes of an endogenous repertoire that proceed upon non-inflammatory conditions prevailing in premalignant tumor lesions. We examined the role of cytolytic capacity on CD8+ T cell fate decisions when primed by tumor cells or by minor histocompatibility antigen-mismatched leukocytes. CD8+ memory commitment was analyzed in Ebag9-deficient mice that exhibit an enhanced tumor cell lysis. This property endowed Ebag9-/- mice with extended control of Tcl-1 oncogene-induced chronic lymphocytic leukemia progression. In Ebag9-/- mice, an expanded memory population was obtained for anti-HY and anti-SV40 T antigen-specific T cells, despite unchanged effector frequencies in the primary response. By comparing the single-cell transcriptomes of CD8+ T cells responding to tumor cell vaccination, we found differential distribution of subpopulations between Ebag9+/+ and Ebag9-/- T cells. In Ebag9-/- cells, these larger clusters contained genes encoding transcription factors regulating memory cell differentiation, along with anti-apoptotic gene functions. Our findings link EBAG9-controlled cytolytic activity and the commitment to the CD8+ memory lineage.
Armin Rehm, Anthea Wirges, Dana Hoser, Cornelius Fischer, Stefanie Herda, Kerstin Gerlach, Sascha Sauer, Gerald Willimsky, Uta E. Höpken
Secondary infections are frequent complications of viral respiratory infections but the potential consequence of SARS-CoV-2 co-infection with common pulmonary pathogens is poorly understood. We report that co-infection of human ACE2 transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following co-infection were associated with alveolar macrophage depletion and treatment with murine GM-CSF reduced lung bacteria numbers and pathology, and partially protected from death. However, therapeutic targeting of interferons, an approach that is effective against influenza co-infections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent co-infection. The results indicate that when seasonal respiratory infections return to pre-pandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.
Tarani Kanta Barman, Amit K. Singh, Jesse L. Bonin, Tanvir N. Nafiz, Sharon L. Salmon, Dennis W. Metzger
Hvcn1 is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of reactive oxygen species (ROS). The increased expression of this channel in some cancers, has led to proposing Hvcn1 antagonists as potential therapeutics.While its role in most leukocytes has been studied in-depth, the function of Hvcn1 in T-cells remains poorly defined. We show that HVCN1 plays a non-redundant role in protecting naïve T-cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T-cells display profound differences during the transition from naïve to primed T-cells, including in the preservation of TCR signaling, cellular division and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naïve CD4+ T-cells reprogram to rescue the glycolytic pathway, naïve CD8+ T-cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation.These observations imply heterogeneity between adaptation of naïve CD4+ and CD8+ T-cells to intracellular acidification during activation.
David Coe, Thanushiyan Poobalasingam, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, Valle Morales, Annalisa Moregola, Nico Mitro, Kenneth C.P. Cheung, Eleanor J. Ward, Suchita Nadkarni, Dunja Aksentijevic, Katiuscia Bianchi, Giuseppe Danilo Norata, Melania Capasso, Federica M. Marelli-Berg
BACKGROUND. Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). METHODS. This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. RESULTS. We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS. Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups. FUNDING. Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR) /COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (T.H.W. and A.C.G); CIHR FDN-143250 (T.H.W.), GA2- 177716 (V.C., A.C.G., T.H.W.), GA1-177703 (A.C.G.) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to A.C.G.).
Roya M. Dayam, Jaclyn C. Law, Rogier L. Goetgebuer, Gary Y.C. Chao, Kento T. Abe, Mitchell Sutton, Naomi Finkelstein, Joanne M. Stempak, Daniel Pereira, David Croitoru, Lily Acheampong, Saima Rizwan, Klaudia Rymaszewski, Raquel Milgrom, Darshini Ganatra, Nathalia V. Batista, Melanie Girard, Irene Lau, Ryan Law, Michelle W. Cheung, Bhavisha Rathod, Julia Kitaygorodsky, Reuben Samson, Queenie Hu, W. Rod Hardy, Nigil Haroon, Robert D. Inman, Vincent Piguet, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Inflammation of the esophageal epithelium is a hallmark of eosinophilic esophagitis (EoE), an emerging chronic allergic disease. Herein, we probed human esophageal epithelial cells at single-cell resolution during homeostasis and EoE. During allergic inflammation, the epithelial differentiation program was blocked, leading to loss of KRT6high differentiated populations and expansion of TOP2high proliferating and DSPhigh, SERPINB3high transitioning populations; however, there was stability of the stem cell–enriched PDPNhigh basal epithelial compartment. This differentiation program blockade was associated with dysregulation of transcription factors, including nuclear receptor signalers, in the most differentiated epithelial cells and altered NOTCH-related cell-to-cell communication. Each epithelial population expressed genes with allergic disease risk variants, supporting their functional interplay. The esophageal epithelium differed notably between EoE in histologic remission and controls, indicating that remission is a transitory state poised to relapse. Collectively, our data uncover the dynamic nature of the inflamed human esophageal epithelium and provide a framework to better understand esophageal health and disease.
Mark Rochman, Ting Wen, Michael Kotliar, Phillip J. Dexheimer, Netali Ben-Baruch Morgenstern, Julie M. Caldwell, Hee-Woong Lim, Marc E. Rothenberg
The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum parasite. Using protein microarrays, levels of IgG to 1,000 P. falciparum antigens were measured in 2,138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase 3 trial, sampled before and at four longitudinal visits after vaccination. One month post-vaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no prevaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8 fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (~11-fold increase). They were strongly cross-correlated and correlated with anti CSP levels, waning similarly over time and re-increasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site and post-vaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.
Dídac Macià, Joseph J. Campo, Gemma Moncunill, Chenjerai Jairoce, Augusto J. Nhabomba, Maximilian Mpina, Hermann Sorgho, David Dosoo, Ousmane Traore, Kwadwo A. Kusi, Nana Aba Williams, Amit Oberai, Arlo Randall, Hector Sanz, Clarissa Valim, Kwaku P. Asante, Seth Owusu-Agyei, Halidou Tinto, Selidji T. Agnandji, Simon Kariuki, Ben Gyan, Claudia Daubenberger, Benjamin Mordmüller, Paula Petrone, Carlota Dobaño
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