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Lymphatics

Lymphatics is an international, peer-reviewed, open access journal on lymphatics and related disorders published quarterly online by MDPI.

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All Articles (102)

Overcoming Microenvironment-Driven Resistance to CAR-T Therapy in Multiple Myeloma

  • Gabriel Saez,
  • Randy Khusial and
  • Heather Kissel
  • + 3 authors

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for relapsed or refractory multiple myeloma (MM), with products such as idecabtagene vicleucel and ciltacabtagene autoleucel achieving high initial response rates, and in selected patient populations, durable treatment-free remission. However, a substantial proportion of patients still experience relapse, including antigen-positive progression, highlighting persistent limitations in long-term disease control across diverse clinical settings. An increasing body of evidence indicates that resistance to CAR-T therapy in MM is driven not only by tumor-intrinsic factors, but also by extrinsic pressures imposed by the bone marrow microenvironment (BMME). This review integrates current understanding of tumor-niche interactions that impair CAR-T persistence, trafficking, and effector function, including immunosuppressive cellular networks, inhibitory cytokine signaling, metabolic constraints, stromal adhesion, antigen modulation, and marrow remodeling. This review further examines emerging therapeutic strategies and next-generation CAR-T platforms.

5 March 2026

Cell-mediated signaling pathways interfering with CAR-T cell efficacy against MM cells. CAR-T cells can be limited by multiple pathways from multiple cell lines within the TME and within BM. MM cells recruit monocytes from peripheral circulation into the TME, and then promote differentiation to M2 cells through production of TGF-β, IL-10, and IL-13. Monocytes in the TME can also differentiate to TAMs which also produce TGF-β and IL-10. This same TGF-β and IL-10, as well as TGF-β from CAFs, suppress CAR-T cell function. TAMs have an additional function by producing IL-6, IL-23, and IL-17, while promoting MM cell survival and function and inhibiting IL-12 and TNFα produced by CAR-T cells, which would otherwise inhibit MM cell function (red arrows).

Bone marrow involvement in B-cell non-Hodgkin lymphoma is an adverse prognostic factor; therefore, its detection is necessary at the time of diagnosis and during follow-up. This study evaluates the concordance between flow cytometry (FC) and bone marrow biopsy (BMB) in detecting bone marrow involvement in B-cell non-Hodgkin lymphomas as well as their prognostic relevance in a Chilean cohort. A total of 202 samples from 172 patients with diffuse large B-cell (DLBCL), follicular (FL), marginal-zone (MZL), and mantle cell (MCL) lymphoma were retrospectively analyzed; all patients underwent simultaneous BMB and FC. Bone marrow involvement was identified in 29% of samples via BMB and in 40% via FC, with an overall concordance of 89% (kappa: 0.75), which was lower in mantle cell lymphoma. Eleven percent of cases showed BMB-FC+ discordance, generally associated with low tumor burden. In survival analyses, the BMB+/FC+ group exhibited shorter overall and progression-free survival, and concordant involvement was associated with a higher risk of mortality and progression, particularly among patients with an intermediate or high IPI. Involvement detected exclusively by FC did not have a significant prognostic impact. These findings support the role of FC as a complementary or alternative diagnostic tool in settings with limited resources, improving sensitivity for detecting bone marrow involvement without compromising clinical relevance.

27 February 2026

Kaplan–Meier survival curves according to bone marrow involvement assessed via BMB and FC: (a) OS of non-infiltrated (BMB-FC-), discordant (BMB-/FC+), and infiltrated (BMB+/FC+) patients; (b) PFS of non-infiltrated (BMB-/FC-), discordant (BMB-/FC+), and infiltrated (BMB+/FC+) patients; (c) OS considering discordant cases among the non-infiltrated patients; and (d) PFS considering discordant cases among the non-infiltrated patients.

Neck Dissection in the Era of Immunotherapy: A Narrative Review

  • Andrea Lorenzi,
  • Carmine Prizio and
  • Narayana Subramaniam
  • + 2 authors

Cervical lymph node metastases are major prognostic determinants in head and neck squamous cell carcinoma (HNSCC), and neck dissection (ND) has long been central to regional control. As ND has evolved from radical to selective procedures, immune checkpoint inhibitors (ICIs) have emerged as a fourth treatment pillar, reframing tumor-draining lymph nodes (TDLNs) as active immune organs rather than passive conduits of metastatic spread. This narrative review synthesizes surgical, immunologic, and translational evidence on how ND and cervical irradiation interact with immunotherapy. It also examines the historical development of ND, the immunologic structure and function of cervical TDLNs, and the use of neoadjuvant, perioperative, and recurrent/metastatic immunotherapy in HNSCC. Preclinical and early clinical observations suggest that ablating or heavily irradiating non-involved nodal basins may attenuate ICI efficacy by disrupting antigen presentation, progenitor exhausted CD8+ T (Tpex) cell pools, and effector recirculation, supporting the conceptual model of an “immune desert neck.” The review critically appraises timing (pre- versus post-immunotherapy ND), response-adapted or de-escalated surgery, and imaging, tissue-based, and circulating biomarkers to guide individualized management. Current evidence does not support abandoning elective or therapeutic ND, but does highlight the need for biomarker-driven, lymphatic-sparing trials to redefine when ND is essential, modifiable, or potentially avoidable in immunotherapy-treated HNSCC.

22 February 2026

Conceptual framework for managing TDLNs in the immunotherapy era [14]. Effective immune checkpoint blockade depends on an intact tumor–lymph node axis, in which TDLNs function as active immune organs that coordinate antigen presentation, expansion of Tpex cells, and effector recirculation. Traditional strategies—elective ND and broad-field elective nodal irradiation—achieve regional control but may simultaneously ablate or chronically damage non-involved nodal basins, creating an “immune desert neck” that attenuates immunotherapy efficacy. HNC, head and neck cancer; ICI, immune checkpoint inhibitor; IO, immunotherapy; LN, lymph node.

Nodes of Contention: The Role of Lymphadenectomy in Adrenocortical Cancer Management

  • Joanna Aldoori,
  • Rajeev Parameswaran and
  • Mechteld C. de Jong

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine malignancy with poor survival outcomes and high recurrence rates. Whilst surgical resection is the cornerstone of curative treatment, the role of lymphadenectomy remains debated. “Nodes of contention” in ACC management center on balancing accurate staging and potential oncologic benefit against added operative time, complexity, and morbidity. We reviewed the available published literature over the last 20 years, including retrospective series, to evaluate the prognostic and therapeutic significance of lymphadenectomy in ACC. Though systematic lymph node dissection improves staging accuracy and may identify patients at higher risk who could benefit from adjuvant therapy, evidence demonstrating a survival benefit is inconsistent. This is largely due to the rarity of the condition, heterogeneity in surgical approaches, and lack of standardized nodal templates. Concerns regarding increased operative morbidity further limit widespread adoption. This review synthesizes current evidence on nodal assessment in ACC and highlights gaps in prospective data. While nodal involvement is a strong prognostic factor, the therapeutic impact of lymphadenectomy remains unclear. Prospective, multicenter trials are urgently needed to define its role in ACC management.

18 February 2026

Lymphatic drainage of the adrenal glands. Abbreviation: IVC—inferior vena cava.

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Lymphatics - ISSN 2813-3307